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1
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Miyamori H, Yokokawa T, Miyakita M, Ozaki K, Goto T, Inoue K, Matsumura S. CRTC1 in Mc4r-Expressing Cells Is Required for Peripheral Metabolism and Systemic Energy Homeostasis. Diabetes 2024; 73:1976-1989. [PMID: 39264819 DOI: 10.2337/db24-0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 09/05/2024] [Indexed: 09/14/2024]
Abstract
Melanocortin-4 receptor (Mc4r) is a G protein-coupled receptor that controls systemic energy balance by regulating food intake and energy expenditure. Although the detailed molecular mechanism remains unclear, the activation of cAMP signaling in Mc4r-expressing cells reportedly suppresses food intake and increases energy expenditure. CREBP-regulated transcriptional coactivator-1 (CRTC1) is selectively expressed in neuronal cells and participates in transcriptional control, thereby contributing to neuronal plasticity and energy homeostasis. Considering the cAMP-dependent regulation of CRTC1 activity, CRTC1 in Mc4r-expressing cells may contribute to energy balance regulation through the melanocortin pathway. In this context, we examined the physiological contribution of CRTC1 in Mc4r-expressing cells to energy metabolism. In this study, mice with CRTC1 deficiency in Mc4r-expressing cells exhibited 1) modest obesity, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperlipidemia; 2) decreased systemic energy expenditure and thermogenesis; 3) suppression of melanocortin agonist-induced adaptation of energy expenditure and food intake; 4) impaired thermogenic programs and oxidative pathway in brown adipose tissue and skeletal muscle; and 5) enhanced lipogenic programs in the liver and white adipose tissue. These results provide novel insights into the molecular mechanisms underlying the regulation of energy balance by the melanocortin system. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Haruka Miyamori
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Takumi Yokokawa
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Motoki Miyakita
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Kazuki Ozaki
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Kazuo Inoue
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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2
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Henry BA, Cowley MA, Andrews ZB, Clarke IJ. Femoral artery infusion of αMSH increases muscle thermogenesis and promotes glucose uptake in ovariectomised ewes. Endocrinology 2024; 166:bqae156. [PMID: 39560101 PMCID: PMC11606653 DOI: 10.1210/endocr/bqae156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/31/2024] [Accepted: 11/18/2024] [Indexed: 11/20/2024]
Abstract
The melanocortin system is fundamental to neural control of energy balance and long-term weight regulation. Recent evidence shows that melanocortins also act at peripheral tissues to regulate metabolism, independent of the brain or the sympathetic nervous system (SNS). One such target is skeletal muscle, which contributes to energy expenditure through changes in adaptive thermogenesis. We aimed to determine 1. whether direct femoral infusion of αMSH could increase muscle heat production independent of SNS activation and 2. if α-MSH-induced skeletal muscle heat production was associated with altered mitochondrial function. Dataloggers were implanted into one hind-leg of ovariectomised ewes and set to record vastus lateralis temperature every 15 mins. A cannula was inserted into one femoral artery for infusion of either αMSH (0.1 μg/ h) or saline. Femoral infusion of αMSH increased (P<0.0001) skeletal muscle heat production, without effect on food intake. State 4 respiration increased (P<0.05) and the respiratory control ratio decreased (P<0.05) in mitochondria isolated from αMSH-treated animals. In addition, femoral infusion of αMSH reduced plasma glucose concentration in the femoral, but not the jugular vein; there was no effect of αMSH treatment on non-esterified fatty acid concentrations. These data suggest that αMSH can act locally to increase glucose uptake. We further show that blockade of the α- and β-adrenergic limbs of the SNS with either phentolamine or propranolol infusion, had no effect on αMSH-induced skeletal muscle heat production. Overall, we show that αMSH acts directly at skeletal muscle to promote glucose uptake and increase energy expenditure via mitochondrial thermogenesis.
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Affiliation(s)
- Belinda A Henry
- Department of Physiology, Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Michael A Cowley
- Department of Physiology, Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Zane B Andrews
- Department of Physiology, Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Iain J Clarke
- Department of Physiology, Monash University, Clayton, VIC 3800, Australia
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Watts CA, Smith J, Giacomino R, Walter D, Jang G, Malik A, Harvey N, Novak CM. Chemogenetic Excitation of Ventromedial Hypothalamic Steroidogenic Factor 1 (SF1) Neurons Increases Muscle Thermogenesis in Mice. Biomolecules 2024; 14:821. [PMID: 39062535 PMCID: PMC11274921 DOI: 10.3390/biom14070821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Allostatic adaptations to a perceived threat are crucial for survival and may tap into mechanisms serving the homeostatic control of energy balance. We previously established that exposure to predator odor (PO) in rats significantly increases skeletal muscle thermogenesis and energy expenditure (EE). Evidence highlights steroidogenic factor 1 (SF1) cells within the central and dorsomedial ventromedial hypothalamus (c/dmVMH) as a modulator of both energy homeostasis and defensive behavior. However, the brain mechanism driving elevated EE and muscle thermogenesis during PO exposure has yet to be elucidated. To assess the ability of SF1 neurons of the c/dmVMH to induce muscle thermogenesis, we used the combined technology of chemogenetics, transgenic mice, temperature transponders, and indirect calorimetry. Here, we evaluate EE and muscle thermogenesis in SF1-Cre mice exposed to PO (ferret odor) compared to transgenic and viral controls. We detected significant increases in muscle temperature, EE, and oxygen consumption following the chemogenetic stimulation of SF1 cells. However, there were no detectable changes in muscle temperature in response to PO in either the presence or absence of chemogenetic stimulation. While the specific role of the VMH SF1 cells in PO-induced thermogenesis remains uncertain, these data establish a supporting role for SF1 neurons in the induction of muscle thermogenesis and EE similar to what is seen after predator threats.
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Affiliation(s)
- Christina A. Watts
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA;
| | - Jordan Smith
- College of Public Health, Kent State University, Kent, OH 44242, USA
| | - Roman Giacomino
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Dinah Walter
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Guensu Jang
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Aalia Malik
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Nicholas Harvey
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Colleen M. Novak
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA;
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
- Brain Health Research Institute, Kent State University, Kent, OH 44242, USA
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Shemery AM, Zendlo M, Kowalski J, Gorrell E, Everett S, Wagner JG, Davis AE, Koch LG, Britton SL, Mul JD, Novak CM. Reduced contextually induced muscle thermogenesis in rats with calorie restriction and lower aerobic fitness but not monogenic obesity. Temperature (Austin) 2023; 10:379-393. [PMID: 37554387 PMCID: PMC10405760 DOI: 10.1080/23328940.2023.2171669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/29/2023] Open
Abstract
We have previously identified predator odor as a potent stimulus activating thermogenesis in skeletal muscle in rats. As this may prove relevant for energy balance and weight loss, the current study investigated whether skeletal muscle thermogenesis was altered with negative energy balance, obesity propensity seen in association with low intrinsic aerobic fitness, and monogenic obesity. First, weight loss subsequent to 3 wk of 50% calorie restriction suppressed the muscle thermogenic response to predator odor. Next, we compared rats bred based on artificial selection for intrinsic aerobic fitness - high- and low-capacity runners (HCR, LCR) - that display robust leanness and obesity propensity, respectively. Aerobically fit HCR showed enhanced predator odor-induced muscle thermogenesis relative to the less-fit LCR. This contrasted with the profound monogenic obesity displayed by rats homozygous for a loss of function mutation in Melanocortin 4 receptor (Mc4rK3a,4X/K314X rats), which showed no discernable deficit in thermogenesis. Taken together, these data imply that body size or obesity per se are not associated with deficient muscle thermogenesis. Rather, the physiological phenotype associated with polygenic obesity propensity may encompass pleiotropic mechanisms in the thermogenic pathway. Adaptive thermogenesis associated with weight loss also likely alters muscle thermogenic mechanisms.
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Affiliation(s)
| | - Meredith Zendlo
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Jesse Kowalski
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Erin Gorrell
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Scott Everett
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Jacob G. Wagner
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Ashley E. Davis
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Lauren G. Koch
- Department of Physiology and Pharmacology, the University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Steven L. Britton
- Department of Anesthesiology, and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Joram D. Mul
- Brain Plasticity Group, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, the Netherlands
| | - Colleen M. Novak
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
- Department of Biological Sciences, Kent State University, Kent, OH, USA
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5
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Heemstra LA, Koch LG, Britton SL, Novak CM. Altered skeletal muscle sarco-endoplasmic reticulum Ca 2+-ATPase calcium transport efficiency after a thermogenic stimulus. Am J Physiol Regul Integr Comp Physiol 2022; 323:R628-R637. [PMID: 36094445 PMCID: PMC9602703 DOI: 10.1152/ajpregu.00173.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 01/22/2023]
Abstract
Exposure to predator threat induces a rapid and robust increase in skeletal muscle thermogenesis in rats. The central nervous system relays threat information to skeletal muscle through activation of the sympathetic nervous system, but muscle mechanisms mediating this thermogenesis remain unidentified. Given the relevance of sarcolipin-mediated futile calcium cycling through the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) pump to mammalian muscle nonshivering thermogenesis, we hypothesized that this plays a role in contextually induced muscle thermogenesis as well. This was assessed by measuring enzymatic activity of SERCA and sarcoplasmic reticulum Ca2+ transport, where the apparent coupling ratio (Ca2+ uptake rate divided by ATPase activity rate at a standard Ca2+ concentration) was predicted to decrease in association with muscle thermogenesis. Sprague-Dawley rats exposed to predator (ferret) odor (PO) showed a rapid decrease in the apparent coupling ratio in the soleus muscle, indicating SERCA uncoupling compared with control-odor-exposed rats. A rat model of high aerobic fitness and elevated muscle thermogenesis also demonstrated soleus muscle SERCA uncoupling relative to their obesity-prone, low-fitness counterparts. Both the high- and low-aerobic fitness rats showed soleus SERCA uncoupling with exposure to PO. Finally, no increase in sarcolipin expression in soleus muscle was detected with PO exposure. This dataset implicates muscle uncoupling of SERCA Ca2+ transport and ATP hydrolysis, likely through altered SERCA or sarcolipin function outside of translational regulation, as one contributor to the muscle thermogenesis provoked by exposure to predator threat. These data support the involvement of SERCA uncoupling in both muscle thermogenic induction and enhanced aerobic capacity.
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Affiliation(s)
- Lydia A Heemstra
- Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Lauren G Koch
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Steven L Britton
- Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Colleen M Novak
- Department of Biological Sciences, Kent State University, Kent, Ohio
- School of Biomedical Sciences, Kent State University, Kent, Ohio
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6
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Wang Q, Zhang B, Stutz B, Liu ZW, Horvath TL, Yang X. Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity. SCIENCE ADVANCES 2022; 8:eabn8092. [PMID: 36044565 PMCID: PMC9432828 DOI: 10.1126/sciadv.abn8092] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 07/14/2022] [Indexed: 05/31/2023]
Abstract
The ventromedial hypothalamus (VMH) is known to regulate body weight and counterregulatory response. However, how VMH neurons regulate lipid metabolism and energy balance remains unknown. O-linked β-d-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), catalyzed by O-GlcNAc transferase (OGT), is considered a cellular sensor of nutrients and hormones. Here, we report that genetic ablation of OGT in VMH neurons inhibits neuronal excitability. Mice with VMH neuron-specific OGT deletion show rapid weight gain, increased adiposity, and reduced energy expenditure, without significant changes in food intake or physical activity. The obesity phenotype is associated with adipocyte hypertrophy and reduced lipolysis of white adipose tissues. In addition, OGT deletion in VMH neurons down-regulates the sympathetic activity and impairs the sympathetic innervation of white adipose tissues. These findings identify OGT in the VMH as a homeostatic set point that controls body weight and underscore the importance of the VMH in regulating lipid metabolism through white adipose tissue-specific innervation.
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Affiliation(s)
- Qi Wang
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA
| | - Bichen Zhang
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA
| | - Bernardo Stutz
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Zhong-Wu Liu
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Tamas L. Horvath
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
- Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xiaoyong Yang
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
- Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA
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Katashima CK, de Oliveira Micheletti T, Braga RR, Gaspar RS, Goeminne LJE, Moura-Assis A, Crisol BM, Brícola RS, Silva VRR, de Oliveira Ramos C, da Rocha AL, Tavares MR, Simabuco FM, Matheus VA, Buscaratti L, Marques-Souza H, Pazos P, Gonzalez-Touceda D, Tovar S, del Carmen García M, Neto JCR, Curi R, Hirabara SM, Brum PC, Prada PO, de Moura LP, Pauli JR, da Silva ASR, Cintra DE, Velloso LA, Ropelle ER. Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism. SCIENCE ADVANCES 2022; 8:eabm7355. [PMID: 35905178 PMCID: PMC9337767 DOI: 10.1126/sciadv.abm7355] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 06/15/2022] [Indexed: 05/31/2023]
Abstract
Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.
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Affiliation(s)
- Carlos Kiyoshi Katashima
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
| | - Thayana de Oliveira Micheletti
- Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Renata Rosseto Braga
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
| | - Rodrigo Stellzer Gaspar
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Ludger J. E. Goeminne
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Alexandre Moura-Assis
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Barbara Moreira Crisol
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
| | - Rafael S. Brícola
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
| | - Vagner Ramon R. Silva
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
| | - Camila de Oliveira Ramos
- Laboratory of Nutritional Genomic, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
| | - Alisson L. da Rocha
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Pretol, São Paulo, Brazil
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Mariana Rosolen Tavares
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Valquiria Aparecida Matheus
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Lucas Buscaratti
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Henrique Marques-Souza
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Patricia Pazos
- Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS) and CIBER Fisiopatología Obesidad y Nutrición (CB 06/03), Instituto de Salud Carlos III (ISCIII, Ministerio de Economía y Competitividad (MINECO), University of Santiago de Compostela, Santiago de Compostela 15782, Spain
| | - David Gonzalez-Touceda
- Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS) and CIBER Fisiopatología Obesidad y Nutrición (CB 06/03), Instituto de Salud Carlos III (ISCIII, Ministerio de Economía y Competitividad (MINECO), University of Santiago de Compostela, Santiago de Compostela 15782, Spain
| | - Sulay Tovar
- Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS) and CIBER Fisiopatología Obesidad y Nutrición (CB 06/03), Instituto de Salud Carlos III (ISCIII, Ministerio de Economía y Competitividad (MINECO), University of Santiago de Compostela, Santiago de Compostela 15782, Spain
| | - María del Carmen García
- Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS) and CIBER Fisiopatología Obesidad y Nutrición (CB 06/03), Instituto de Salud Carlos III (ISCIII, Ministerio de Economía y Competitividad (MINECO), University of Santiago de Compostela, Santiago de Compostela 15782, Spain
| | - Jose Cesar Rosa Neto
- Immunometabolism Research Group, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-900, Brazil
| | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-900, Brazil
- Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Sandro Massao Hirabara
- Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Patrícia Chakur Brum
- School of Physical Education and Sport, University of São Paulo (USP), São Paulo 05508-030, Brazil
| | - Patrícia Oliveira Prada
- Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Leandro P. de Moura
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
- CEPECE—Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
- CEPECE—Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
| | - Adelino S. R. da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Pretol, São Paulo, Brazil
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Dennys Esper Cintra
- Laboratory of Nutritional Genomic, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
| | - Licio A. Velloso
- Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeria, São Paulo 13484-350, Brazil
- Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- CEPECE—Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
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8
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Watts CA, Haupt A, Smith J, Welch E, Malik A, Giacomino R, Walter D, Mavundza N, Shemery A, Caldwell HK, Novak CM. Measuring Skeletal Muscle Thermogenesis in Mice and Rats. J Vis Exp 2022:10.3791/64264. [PMID: 35969093 PMCID: PMC9969793 DOI: 10.3791/64264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Skeletal muscle thermogenesis provides a potential avenue for better understanding metabolic homeostasis and the mechanisms underlying energy expenditure. Surprisingly little evidence is available to link the neural, myocellular, and molecular mechanisms of thermogenesis directly to measurable changes in muscle temperature. This paper describes a method in which temperature transponders are utilized to retrieve direct measurements of mouse and rat skeletal muscle temperature. Remote transponders are surgically implanted within the muscle of mice and rats, and the animals are given time to recover. Mice and rats must then be repeatedly habituated to the testing environment and procedure. Changes in muscle temperature are measured in response to pharmacological or contextual stimuli in the home cage. Muscle temperature can also be measured during prescribed physical activity (i.e., treadmill walking at a constant speed) to factor out changes in activity as contributors to the changes in muscle temperature induced by these stimuli. This method has been successfully used to elucidate mechanisms underlying muscle thermogenic control at the level of the brain, sympathetic nervous system, and skeletal muscle. Provided are demonstrations of this success using predator odor (PO; ferret odor) as a contextual stimulus and injections of oxytocin (Oxt) as a pharmacological stimulus, where predator odor induces muscle thermogenesis, and Oxt suppresses muscle temperature. Thus, these datasets display the efficacy of this method in detecting rapid changes in muscle temperature.
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Affiliation(s)
| | - Alexandra Haupt
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Jordan Smith
- College of Public Health, Kent State University, Kent, OH, USA
| | - Emily Welch
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Aalia Malik
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Roman Giacomino
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Dinah Walter
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | | | - Ashley Shemery
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Heather K. Caldwell
- School of Biomedical Sciences, Kent State University, Kent, OH, USA,Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Colleen M. Novak
- School of Biomedical Sciences, Kent State University, Kent, OH, USA,Department of Biological Sciences, Kent State University, Kent, OH, USA
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9
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Choi JH, Kim MS. Homeostatic Regulation of Glucose Metabolism by the Central Nervous System. Endocrinol Metab (Seoul) 2022; 37:9-25. [PMID: 35255598 PMCID: PMC8901968 DOI: 10.3803/enm.2021.1364] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/07/2022] [Indexed: 12/04/2022] Open
Abstract
Evidence for involvement of the central nervous system (CNS) in the regulation of glucose metabolism dates back to the 19th century, although the majority of the research on glucose metabolism has focused on the peripheral metabolic organs. Due to recent advances in neuroscience, it has now become clear that the CNS is indeed vital for maintaining glucose homeostasis. To achieve normoglycemia, specific populations of neurons and glia in the hypothalamus sense changes in the blood concentrations of glucose and of glucoregulatory hormones such as insulin, leptin, glucagon-like peptide 1, and glucagon. This information is integrated and transmitted to other areas of the brain where it eventually modulates various processes in glucose metabolism (i.e., hepatic glucose production, glucose uptake in the brown adipose tissue and skeletal muscle, pancreatic insulin and glucagon secretion, renal glucose reabsorption, etc.). Errors in these processes lead to hyper- or hypoglycemia. We here review the current understanding of the brain regulation of glucose metabolism.
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Affiliation(s)
- Jong Han Choi
- Division of Endocrinology and Metabolism, Konkuk University Medical Center, Seoul,
Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
- Appeptite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul,
Korea
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10
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Myers MG, Affinati AH, Richardson N, Schwartz MW. Central nervous system regulation of organismal energy and glucose homeostasis. Nat Metab 2021; 3:737-750. [PMID: 34158655 DOI: 10.1038/s42255-021-00408-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/12/2021] [Indexed: 02/05/2023]
Abstract
Growing evidence implicates the brain in the regulation of both immediate fuel availability (for example, circulating glucose) and long-term energy stores (that is, adipose tissue mass). Rather than viewing the adipose tissue and glucose control systems separately, we suggest that the brain systems that control them are components of a larger, highly integrated, 'fuel homeostasis' control system. This conceptual framework, along with new insights into the organization and function of distinct neuronal systems, provides a context within which to understand how metabolic homeostasis is achieved in both basal and postprandial states. We also review evidence that dysfunction of the central fuel homeostasis system contributes to the close association between obesity and type 2 diabetes, with the goal of identifying more effective treatment options for these common metabolic disorders.
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Affiliation(s)
- Martin G Myers
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Alison H Affinati
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Nicole Richardson
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Michael W Schwartz
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA.
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11
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Affinati AH, Sabatini PV, True C, Tomlinson AJ, Kirigiti M, Lindsley SR, Li C, Olson DP, Kievit P, Myers MG, Rupp AC. Cross-species analysis defines the conservation of anatomically segregated VMH neuron populations. eLife 2021; 10:69065. [PMID: 34018926 PMCID: PMC8184210 DOI: 10.7554/elife.69065] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/14/2021] [Indexed: 12/14/2022] Open
Abstract
The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing translating ribosome affinity purification with RNA-sequencing (TRAP-seq) data with single-nucleus RNA-sequencing (snRNA-seq) data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of six major genetically and anatomically differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.
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Affiliation(s)
- Alison H Affinati
- Department of Internal Medicine, University of Michigan, Ann Arbor, United States
| | - Paul V Sabatini
- Department of Internal Medicine, University of Michigan, Ann Arbor, United States
| | - Cadence True
- Oregon National Primate Research Center, Beaverton, United States
| | - Abigail J Tomlinson
- Department of Internal Medicine, University of Michigan, Ann Arbor, United States
| | - Melissa Kirigiti
- Oregon National Primate Research Center, Beaverton, United States
| | - Sarah R Lindsley
- Oregon National Primate Research Center, Beaverton, United States
| | - Chien Li
- Novo Nordisk Research Center, Seattle, United States
| | - David P Olson
- Department of Pediatrics, University of Michigan, Ann Arbor, United States
| | - Paul Kievit
- Oregon National Primate Research Center, Beaverton, United States
| | - Martin G Myers
- Department of Internal Medicine, University of Michigan, Ann Arbor, United States
| | - Alan C Rupp
- Department of Internal Medicine, University of Michigan, Ann Arbor, United States
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12
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Sutton Hickey AK, Goforth PB, Gonzalez IE, Dell'Orco J, Pei H, Myers MG, Olson DP. Melanocortin 3 receptor-expressing neurons in the ventromedial hypothalamus promote glucose disposal. Proc Natl Acad Sci U S A 2021; 118:e2103090118. [PMID: 33827930 PMCID: PMC8053962 DOI: 10.1073/pnas.2103090118] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The ventromedial hypothalamus (VMH) is a critical neural node that senses blood glucose and promotes glucose utilization or mobilization during hypoglycemia. The VMH neurons that control these distinct physiologic processes are largely unknown. Here, we show that melanocortin 3 receptor (Mc3R)-expressing VMH neurons (VMHMC3R) sense glucose changes both directly and indirectly via altered excitatory input. We identify presynaptic nodes that potentially regulate VMHMC3R neuronal activity, including inputs from proopiomelanocortin (POMC)-producing neurons in the arcuate nucleus. We find that VMHMC3R neuron activation blunts, and their silencing enhances glucose excursion following a glucose load. Overall, these findings demonstrate that VMHMC3R neurons are a glucose-responsive hypothalamic subpopulation that promotes glucose disposal upon activation; this highlights a potential site for targeting dysregulated glycemia.
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Affiliation(s)
- Amy K Sutton Hickey
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Paulette B Goforth
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Ian E Gonzalez
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - James Dell'Orco
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Hongjuan Pei
- Division of Endocrinology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Martin G Myers
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
| | - David P Olson
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
- Division of Endocrinology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109
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13
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McMillan TR, Forster MAM, Short LI, Rudecki AP, Cline DL, Gray SL. Melanotan II, a melanocortin agonist, partially rescues the impaired thermogenic capacity of pituitary adenylate cyclase-activating polypeptide deficient mice. Exp Physiol 2020; 106:427-437. [PMID: 33332767 DOI: 10.1113/ep088838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/27/2020] [Indexed: 12/16/2022]
Abstract
NEW FINDINGS What is the central question of this study? Can chronic treatment of pituitary adenylate cyclase-activating polypeptide (PACAP) deficient mice with the melanocortin agonist melanotan II during cold acclimation rescue the impaired thermogenic capacity previously observed in PACAP deficient mice? What is the main finding and its importance? Using a genetic model of PACAP deficiency, this study provides evidence that PACAP acts upstream of the melanocortin system in regulating sympathetic nerve activity to brown adipose tissue in mice. ABSTRACT Impaired adipose tissue function in obesity, including reduced thermogenic potential, has detrimental consequences for metabolic health. Hormonal regulation of adaptive thermogenesis is being explored as a potential therapeutic target for human obesity. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide expressed in nuclei of the hypothalamus known to regulate energy expenditure, and functional studies reveal a role for PACAP in the central regulation of thermogenesis, although mechanisms are not well understood. We hypothesized that PACAP acts upstream of the melanocortin system to regulate sympathetic nerve activity to stimulate thermogenesis. To assess this, female PACAP-/- and PACAP+/+ mice were given daily peripheral injections of a melanocortin receptor agonist, melanotan II (MTII), for 3 weeks during cold acclimation, and the effect of MTII on thermogenic capacity and adipose tissue remodelling was examined by physiological and histological analyses. MTII partially rescued the impaired thermogenic capacity in PACAP-/- mice as compared to PACAP+/+ mice as determined by measuring noradrenaline-induced metabolic rate. In addition, MTII treatment during cold acclimation corrected the previously identified deficit in lipid utilization in response to adrenergic stimulation in PACAP-/- null mice, suggesting impaired lipid mobilization may contribute to the impaired thermogenic capacity of PACAP-/- mice. Results presented here provide physiological evidence to suggest that PACAP acts upstream of melanocortin receptors to facilitate sympathetically induced mechanisms of adaptive thermogenesis in response to cold acclimation.
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Affiliation(s)
- Thecla Rae McMillan
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
| | - Maeghan A M Forster
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
| | - Landon I Short
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
| | - Alexander P Rudecki
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
| | - Daemon L Cline
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
| | - Sarah L Gray
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
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14
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Shi Z, Qin M, Huang L, Xu T, Chen Y, Hu Q, Peng S, Peng Z, Qu LN, Chen SG, Tuo QH, Liao DF, Wang XP, Wu RR, Yuan TF, Li YH, Liu XM. Human torpor: translating insights from nature into manned deep space expedition. Biol Rev Camb Philos Soc 2020; 96:642-672. [PMID: 33314677 DOI: 10.1111/brv.12671] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/09/2020] [Accepted: 11/17/2020] [Indexed: 12/12/2022]
Abstract
During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.
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Affiliation(s)
- Zhe Shi
- National Clinical Research Center for Mental Disorders, and Department of Psychaitry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.,Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.,Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China
| | - Meng Qin
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Lu Huang
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, 510632, China
| | - Tao Xu
- Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Ying Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Qin Hu
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100024, China
| | - Sha Peng
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Zhuang Peng
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Li-Na Qu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China
| | - Shan-Guang Chen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China
| | - Qin-Hui Tuo
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Duan-Fang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Xiao-Ping Wang
- National Clinical Research Center for Mental Disorders, and Department of Psychaitry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Ren-Rong Wu
- National Clinical Research Center for Mental Disorders, and Department of Psychaitry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Ti-Fei Yuan
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226000, China
| | - Ying-Hui Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China
| | - Xin-Min Liu
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.,Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
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15
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Mukherjee SD, Koch LG, Britton SL, Novak CM. Aerobic capacity modulates adaptive thermogenesis: Contribution of non-resting energy expenditure. Physiol Behav 2020; 225:113048. [PMID: 32628949 PMCID: PMC7594631 DOI: 10.1016/j.physbeh.2020.113048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/17/2020] [Accepted: 07/02/2020] [Indexed: 11/19/2022]
Abstract
Decreases in energy stores requires negative energy balance where caloric expenditure exceeds energy intake, which can induce adaptive thermogenesis-the reduction of energy expenditure (EE) beyond that accounted for by the weight lost. Adaptive thermogenesis varies between individuals. The component of total daily EE responsible for the interindividual variation in adaptive thermogenesis was investigated in this study, using a rat model that differs in obesity propensity and physical activity. Total daily EE and physical activity were examined before and after 21 days of 50% calorie restriction in male and female rats with lean and obesity-prone phenotypes-rats selectively bred for high and low intrinsic aerobic capacity (HCR and LCR, respectively). Calorie restriction significantly decreased EE more than was predicted by loss of weight and lean mass, demonstrating adaptive thermogenesis. Within sex, HCR and LCR did not significantly differ in resting EE. However, the calorie restriction-induced suppression in non-resting EE, which includes activity EE, was significantly greater in HCR than in LCR; this phenotypic difference was significant for both male and female rats. Calorie restriction also significantly suppressed physical activity levels more in HCR than LCR. When VO2max was assessed in male rats, calorie restriction significantly decreased O2 consumption without significantly affecting running performance (running time, distance), indicating increased energy efficiency. Percent weight loss did not significantly differ between groups. Altogether, these results suggest that individual differences in calorie restriction-induced adaptive thermogenesis may be accounted for by variation in aerobic capacity. Moreover, it is likely that activity EE, not resting or basal metabolism, may explain or predict the variation in individuals' adaptive thermogenesis.
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Affiliation(s)
- Sromona Dudiki Mukherjee
- Department of Biological Sciences; Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, United States.
| | - Lauren G Koch
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
| | - Steven L Britton
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States; Department of Anesthesiology, and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Colleen M Novak
- Department of Biological Sciences; School of Biomedical Sciences, Kent State University, Kent, Ohio, United States
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16
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Hainer V, Aldhoon Hainerová I, Kunešová M, Taxová Braunerová R, Zamrazilová H, Bendlová B. Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R). Physiol Res 2020; 69:S245-S254. [PMID: 33094623 DOI: 10.33549/physiolres.934512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.
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Affiliation(s)
- V Hainer
- Obesity Management Center, Institute of Endocrinology, Prague, Czech Republic.
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17
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Holland J, Sorrell J, Yates E, Smith K, Arbabi S, Arnold M, Rivir M, Morano R, Chen J, Zhang X, Dimarchi R, Woods SC, Sanchez-Gurmaches J, Wohleb E, Perez-Tilve D. A Brain-Melanocortin-Vagus Axis Mediates Adipose Tissue Expansion Independently of Energy Intake. Cell Rep 2020; 27:2399-2410.e6. [PMID: 31116984 PMCID: PMC6550338 DOI: 10.1016/j.celrep.2019.04.089] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/18/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023] Open
Abstract
The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing sympathetic nervous system input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here, we demonstrate that reduction of brain-melanocortin signaling actively promotes fat mass gain by activating the lipogenic program and adipocyte and endothelial cell proliferation in white fat depots independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. Those vagally regulated obesogenic signals also contribute to the fat mass gain following chronic high-fat diet feeding. These data reveal a physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity. Brain-melanocortin signaling controls fat mass indirectly by regulating energy balance and by direct control of lipid mobilization from adipose tissue via sympathetic nervous system activity. Holland et al. show that reduced brain-melanocortin signaling promotes white adipose tissue expansion via signals conveyed by efferent innervation of the vagus nerve.
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Affiliation(s)
- Jenna Holland
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joyce Sorrell
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Emily Yates
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kathleen Smith
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Shahriar Arbabi
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Myrtha Arnold
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - Marita Rivir
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rachel Morano
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jenny Chen
- Genomics, Epigenomics and Sequencing Core, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Xiang Zhang
- Genomics, Epigenomics and Sequencing Core, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Richard Dimarchi
- Novo Nordisk Research Center Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
| | - Stephen C Woods
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joan Sanchez-Gurmaches
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Endocrinology and Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA
| | - Eric Wohleb
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Diego Perez-Tilve
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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18
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Flak JN, Goforth PB, Dell’Orco J, Sabatini PV, Li C, Bozadjieva N, Sorensen M, Valenta A, Rupp A, Affinati AH, Cras-Méneur C, Ansari A, Sacksner J, Kodur N, Sandoval DA, Kennedy RT, Olson DP, Myers MG. Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin. J Clin Invest 2020; 130:2943-2952. [PMID: 32134398 PMCID: PMC7260001 DOI: 10.1172/jci134135] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 02/20/2020] [Indexed: 12/14/2022] Open
Abstract
To identify neurons that specifically increase blood glucose from among the diversely functioning cell types in the ventromedial hypothalamic nucleus (VMN), we studied the cholecystokinin receptor B-expressing (CCKBR-expressing) VMN targets of glucose-elevating parabrachial nucleus neurons. Activation of these VMNCCKBR neurons increased blood glucose. Furthermore, although silencing the broader VMN decreased energy expenditure and promoted weight gain without altering blood glucose levels, silencing VMNCCKBR neurons decreased hIepatic glucose production, insulin-independently decreasing blood glucose without altering energy balance. Silencing VMNCCKBR neurons also impaired the counterregulatory response to insulin-induced hypoglycemia and glucoprivation and replicated hypoglycemia-associated autonomic failure. Hence, VMNCCKBR cells represent a specialized subset of VMN cells that function to elevate glucose. These cells not only mediate the allostatic response to hypoglycemia but also modulate the homeostatic setpoint for blood glucose in an insulin-independent manner, consistent with a role for the brain in the insulin-independent control of glucose homeostasis.
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Affiliation(s)
| | - Paulette B. Goforth
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | - Chien Li
- Novo Nordisk, Seattle, Washington, USA
| | | | | | | | | | | | | | | | | | | | | | | | - David P. Olson
- Division of Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
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19
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Gorrell E, Shemery A, Kowalski J, Bodziony M, Mavundza N, Titus AR, Yoder M, Mull S, Heemstra LA, Wagner JG, Gibson M, Carey O, Daniel D, Harvey N, Zendlo M, Rich M, Everett S, Gavini CK, Almundarij TI, Lorton D, Novak CM. Skeletal muscle thermogenesis induction by exposure to predator odor. J Exp Biol 2020; 223:jeb218479. [PMID: 32165434 PMCID: PMC7174837 DOI: 10.1242/jeb.218479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 03/02/2020] [Indexed: 01/07/2023]
Abstract
Non-shivering thermogenesis can promote negative energy balance and weight loss. In this study, we identified a contextual stimulus that induces rapid and robust thermogenesis in skeletal muscle. Rats exposed to the odor of a natural predator (ferret) showed elevated skeletal muscle temperatures detectable as quickly as 2 min after exposure, reaching maximum thermogenesis of >1.5°C at 10-15 min. Mice exhibited a similar thermogenic response to the same odor. Ferret odor induced a significantly larger and qualitatively different response from that of novel or aversive odors, fox odor or moderate restraint stress. Exposure to predator odor increased energy expenditure, and both the thermogenic and energetic effects persisted when physical activity levels were controlled. Predator odor-induced muscle thermogenesis is subject to associative learning as exposure to a conditioned stimulus provoked a rise in muscle temperature in the absence of the odor. The ability of predator odor to induce thermogenesis is predominantly controlled by sympathetic nervous system activation of β-adrenergic receptors, as unilateral sympathetic lumbar denervation and a peripherally acting β-adrenergic antagonist significantly inhibited predator odor-induced muscle thermogenesis. The potential survival value of predator odor-induced changes in muscle physiology is reflected in an enhanced resistance to running fatigue. Lastly, predator odor-induced muscle thermogenesis imparts a meaningful impact on energy expenditure as daily predator odor exposure significantly enhanced weight loss with mild calorie restriction. This evidence signifies contextually provoked, centrally mediated muscle thermogenesis that meaningfully impacts energy balance.
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Affiliation(s)
- Erin Gorrell
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Ashley Shemery
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Jesse Kowalski
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Miranda Bodziony
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Nhlalala Mavundza
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Amber R Titus
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Mark Yoder
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Sarah Mull
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Lydia A Heemstra
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Jacob G Wagner
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Megan Gibson
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Olivia Carey
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Diamond Daniel
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Nicholas Harvey
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Meredith Zendlo
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Megan Rich
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Scott Everett
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Chaitanya K Gavini
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Tariq I Almundarij
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, PO Box 6622, Buraidah 51452, Saudi Arabia
| | - Diane Lorton
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Colleen M Novak
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
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20
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Doslikova B, Tchir D, McKinty A, Zhu X, Marks DL, Baracos VE, Colmers WF. Convergent neuronal projections from paraventricular nucleus, parabrachial nucleus, and brainstem onto gastrocnemius muscle, white and brown adipose tissue in male rats. J Comp Neurol 2019; 527:2826-2842. [PMID: 31045239 DOI: 10.1002/cne.24710] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 01/06/2023]
Abstract
When energy balance is altered by aerobic exercise, starvation, and cold exposure, for example, there appears to be coordination of the responses of skeletal muscle, white adipose (WAT), and brown adipose (BAT) tissues. We hypothesized that WAT, BAT, and skeletal muscle may share an integrated regulation by the central nervous system (CNS); specifically, that neurons in brain regions associated with energy balance would possess neuroanatomical connections to permit coordination of multiple, complementary responses in these downstream tissues. To study this, we used trans-neuronal viral retrograde tract tracing, using isogenic strains of pseudorabies virus (PRV) with distinct fluorescent reporters (either eGFP or mRFP), injected pairwise into male rat gastrocnemius, subcutaneous WAT and interscapular BAT, coupled with neurochemical characterization of specific cell populations for cocaine- and amphetamine-related transcript (CART), oxytocin (OX), corticotrophin releasing hormone (CRH) and calcitonin gene-related peptide (CGRP). Cells in the paraventricular (PVN) and parabrachial (PBN) nuclei and brainstem showed dual projections to muscle + WAT, muscle + BAT, and WAT + BAT. Dual PRV-labeled cells were found in parvocellular, magnocellular and descending/pre-autonomic regions of the PVN, and multiple structural divisions of the PBN and brainstem. In most PBN subdivisions, more than 50% of CGRP cells dually projected to muscle + WAT and muscle + BAT. Similarly, 31-68% of CGRP cells projected both to WAT + BAT. However, dual PRV-labeled cells in PVN only occasionally expressed OX or CRH but not CART. These studies reveal for the first time both separate and shared outflow circuitries among skeletal muscle and subcutaneous WAT and BAT.
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Affiliation(s)
- Barbora Doslikova
- Department of Pharmacology, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Devan Tchir
- Department of Pharmacology, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Amanda McKinty
- Department of Pharmacology, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Xinxia Zhu
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon
| | - Daniel L Marks
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon
| | - Vickie E Baracos
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - William F Colmers
- Department of Pharmacology, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
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21
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Alessio N, Squillaro T, Monda V, Peluso G, Monda M, Melone MAB, Galderisi U, Di Bernardo G. Circulating factors present in the sera of naturally skinny people may influence cell commitment and adipocyte differentiation of mesenchymal stromal cells. World J Stem Cells 2019; 11:180-195. [PMID: 30949296 PMCID: PMC6441938 DOI: 10.4252/wjsc.v11.i3.180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 01/28/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Research on physiopathology of obesity may receive new hints from studies on skinny people (SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements.
AIM To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells (MSCs).
METHODS We isolated MSCs from bone marrow of healthy donors with both normal body mass index (BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people (NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation.
RESULTS SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation.
CONCLUSION Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.
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Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Tiziana Squillaro
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Vincenzo Monda
- Department of Experimental Medicine, Human Physiology and Unit of Dietetic and Sports Medicine Section, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | | | - Marcellino Monda
- Department of Experimental Medicine, Human Physiology and Unit of Dietetic and Sports Medicine Section, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Mariarosa AB Melone
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Umberto Galderisi
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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22
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Clark KS, Coleman C, Shelton R, Heemstra LA, Novak CM. Caffeine enhances activity thermogenesis and energy expenditure in rats. Clin Exp Pharmacol Physiol 2019; 46:475-482. [PMID: 30620415 DOI: 10.1111/1440-1681.13065] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 12/06/2018] [Accepted: 12/27/2018] [Indexed: 10/27/2022]
Abstract
Caffeine and its derivatives have been used, alone and in combination with other phytochemicals, as weight-loss supplements. Caffeine affects several physiological and behavioural aspects of energy balance, including increasing locomotor activity. This study investigates the potential for caffeine to enhance activity thermogenesis and energy expenditure (EE) even when activity level is held constant. To do this, EE and muscle thermogenesis were measured in rats during treadmill walking regimens, with and without caffeine (25 mg/kg, ip). Activity-related EE was significantly increased throughout the treadmill walking protocol. Muscle heat dissipation, on the other hand, was significantly increased by caffeine only at the end of the 25-minute treadmill test. This study demonstrates that caffeine increases the caloric cost of physical activity, compared to the caloric cost of that same physical activity without caffeine, implicating decreased muscle work efficiency. Combined with the known ability of caffeine to increase locomotor activity, the decreased locomotor efficiency imparted by caffeine may further augment the potential for caffeine to enhance caloric expenditure.
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Affiliation(s)
| | - Claire Coleman
- Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Rhiannon Shelton
- Colorado School of Public Health, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Lydia A Heemstra
- Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Colleen M Novak
- Department of Biological Sciences, Kent State University, Kent, Ohio.,School of Biomedical Sciences, Kent State University, Kent, Ohio
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23
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van Iersel L, Brokke KE, Adan RAH, Bulthuis LCM, van den Akker ELT, van Santen HM. Pathophysiology and Individualized Treatment of Hypothalamic Obesity Following Craniopharyngioma and Other Suprasellar Tumors: A Systematic Review. Endocr Rev 2019; 40:193-235. [PMID: 30247642 DOI: 10.1210/er.2018-00017] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 06/25/2018] [Indexed: 12/26/2022]
Abstract
The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Herein, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. Additionally, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017. The search yielded 1866 publications, of which 40 were included. Of these 40 studies, we identified four modalities for intervention (i.e., lifestyle, dietary, pharmacotherapeutic, or surgical) within six clinical domains (i.e., psychosocial disorders, hyperphagia, sleep disturbances, decreased energy expenditure, hyperinsulinemia, and hypopituitarism). We used the findings from our systematic review, in addition to current knowledge on the pathophysiology of HO, to develop an evidence-based treatment algorithm for patients with HO caused by CP or other suprasellar tumors. Although the individual effects of the HO interventions were modest, beneficial individual effects may be achieved when the pathophysiologic background and correct clinical domain are considered. These two aspects can be combined in an individualized treatment algorithm with a stepwise approach for each clinical domain. Recently elucidated targets for HO intervention were also explored to improve future management of HO for patients with CP and other suprasellar tumors.
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Affiliation(s)
- Laura van Iersel
- Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Karen E Brokke
- Medical Sciences, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands
| | - Roger A H Adan
- Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, Netherlands.,Institute for Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lauren C M Bulthuis
- Medical Sciences, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands
| | - Erica L T van den Akker
- Department of Pediatric Endocrinology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
| | - Hanneke M van Santen
- Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
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24
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Yuting Y, Lifeng F, Qiwei H. Secreted modular calcium-binding protein 2 promotes high fat diet (HFD)-induced hepatic steatosis through enhancing lipid deposition, fibrosis and inflammation via targeting TGF-β1. Biochem Biophys Res Commun 2018; 509:48-55. [PMID: 30581002 DOI: 10.1016/j.bbrc.2018.12.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 12/02/2018] [Indexed: 12/15/2022]
Abstract
The molecular mechanism revealing the pathogenesis of non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, remains to be investigated. In the study, we found that secreted modular calcium-binding protein 2 (SMOC2), which belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins, functioned as a positive modulator of NAFLD. SMOC2 expression was markedly up-regulated in human liver samples with NAFLD, and in hepatic tissues of mice fed with HFD. SMOC2 knockout in mice significantly attenuated metabolic disorders, insulin resistance, glucose intolerance and lipid deposition in mice challenged with HFD. Moreover, liver fibrosis induced by HFD was clearly ameliorated by SMOC2 deficiency mainly through inhibiting transforming growth factor (TGF)-β1 expression. Additionally, hepatic inflammatory response triggered by HFD was also improved in SMOC2-knockout mice via inactivating nuclear factor-κB (NF-κB). Mechanically, SMOC2 could interact with TGF-β1, and SMOC2 overexpression markedly increased TGF-β1 in mouse primary hepatocytes, which played an essential role in regulating hepatic steatosis. In conclusion, we provided proof that blocking SMOC2 might be a promising strategy for preventing NAFLD through the interaction with TGF-β1.
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Affiliation(s)
- Yun Yuting
- Department of Gastroenterology, Inner Mongolia People's Hospital, Hohhot City, 010020, China
| | - Feng Lifeng
- Department of Hepatobiliary Surgery, Shaanxi Shangluo Central Hospital, Shangluo, 726000, China
| | - Hao Qiwei
- Department of General Surgery II Ward, Second Hospital of Yulin City, Yulin, 719000, China.
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25
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Abstract
The hypothalamus is the brain region responsible for the maintenance of energetic homeostasis. The regulation of this process arises from the ability of the hypothalamus to orchestrate complex physiological responses such as food intake and energy expenditure, circadian rhythm, stress response, and fertility. Metabolic alterations such as obesity can compromise these hypothalamic regulatory functions. Alterations in circadian rhythm, stress response, and fertility further contribute to aggravate the metabolic dysfunction of obesity and contribute to the development of chronic disorders such as depression and infertility.At cellular level, obesity caused by overnutrition can damage the hypothalamus promoting inflammation and impairing hypothalamic neurogenesis. Furthermore, hypothalamic neurons suffer apoptosis and impairment in synaptic plasticity that can compromise the proper functioning of the hypothalamus. Several factors contribute to these phenomena such as ER stress, oxidative stress, and impairments in autophagy. All these observations occur at the same time and it is still difficult to discern whether inflammatory processes are the main drivers of these cellular dysfunctions or if the hypothalamic hormone resistance (insulin, leptin, and ghrelin) can be pinpointed as the source of several of these events.Understanding the mechanisms that underlie the pathophysiology of obesity in the hypothalamus is crucial for the development of strategies that can prevent or attenuate the deleterious effects of obesity.
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26
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Fuller-Jackson JP, Henry BA. Adipose and skeletal muscle thermogenesis: studies from large animals. J Endocrinol 2018; 237:R99-R115. [PMID: 29703782 DOI: 10.1530/joe-18-0090] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/05/2018] [Indexed: 12/30/2022]
Abstract
The balance between energy intake and energy expenditure establishes and preserves a 'set-point' body weight. The latter is comprised of three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis is defined as the cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue (BAT), wherein uncoupling protein 1 (UCP1) creates a proton leak across the inner mitochondrial membrane, diverting protons away from ATP synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis can occur independent of UCP1. Beige adipocytes have been shown to produce heat via UCP1 as well as via both futile creatine and calcium cycling pathways. On the other hand, the UCP1 homologue UCP3 is abundant in skeletal muscle and post-prandial thermogenesis has been associated with UCP3 and the futile calcium cycling. This review will focus on the differential contributions of adipose tissue and skeletal muscle in determining total thermogenic output and energy expenditure in large mammals. Sheep and pigs do not have a circumscribed brown fat depot but rather possess white fat depots that contain brown and beige adipocytes interspersed amongst white adipose tissue. This is representative of humans, where brown, beige and white adipocytes have been identified in the neck and supraclavicular regions. This review will describe the mechanisms of thermogenesis in pigs and sheep and the relative roles of skeletal muscle and adipose tissue thermogenesis in controlling body weight in larger mammals.
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Affiliation(s)
| | - Belinda A Henry
- Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria, Australia
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27
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Smith JK. Exercise, Obesity and CNS Control of Metabolic Homeostasis: A Review. Front Physiol 2018; 9:574. [PMID: 29867590 PMCID: PMC5965103 DOI: 10.3389/fphys.2018.00574] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 04/30/2018] [Indexed: 01/12/2023] Open
Abstract
This review details the manner in which the central nervous system regulates metabolic homeostasis in normal weight and obese rodents and humans. It includes a review of the homeostatic contributions of neurons located in the hypothalamus, the midbrain and limbic structures, the pons and the medullary area postrema, nucleus tractus solitarius, and vagus nucleus, and details how these brain regions respond to circulating levels of orexigenic hormones, such as ghrelin, and anorexigenic hormones, such as glucagon-like peptide 1 and leptin. It provides an insight as to how high intensity exercise may improve homeostatic control in overweight and obese subjects. Finally, it provides suggestions as to how further progress can be made in controlling the current pandemic of obesity and diabetes.
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Affiliation(s)
- John K Smith
- Departments of Academic Affairs and Biomedical Science, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
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28
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Gavini CK, Britton SL, Koch LG, Novak CM. Inherently Lean Rats Have Enhanced Activity and Skeletal Muscle Response to Central Melanocortin Receptors. Obesity (Silver Spring) 2018; 26:885-894. [PMID: 29566460 PMCID: PMC5916025 DOI: 10.1002/oby.22166] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 02/03/2018] [Accepted: 02/05/2018] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Activity thermogenesis and energy expenditure (EE) are elevated in intrinsically lean rats (high-capacity runners [HCR]) and are also stimulated by melanocortin receptor activation in the ventromedial hypothalamus (VMH). This study determined whether HCR are more responsive to central modulation of activity EE compared with low-capacity runners (LCR). METHODS HCR and LCR rats received intra-VMH microinjections of melanotan II (MTII), a mixed melanocortin receptor agonist. Changes in EE, respiratory exchange ratio, activity EE, muscle heat, norepinephrine turnover, and muscle energetic modulators were compared. RESULTS HCR were significantly more responsive to intra-VMH MTII-induced changes in EE, activity EE, norepinephrine turnover to some muscle subgroups, and muscle mRNA expression of some energetic modulators. Though HCR had high muscle activity thermogenesis, limited MTII-induced modulation of muscle thermogenesis during activity was seen in LCR only. CONCLUSIONS An inherently lean, high-capacity rat phenotype showed elevated response to central melanocortin stimulation of activity EE and use of fat as fuel. This may be driven by sympathetic outflow to skeletal muscle, which was elevated after MTII. Central melanocortin receptor activation also altered skeletal muscle energetic modulators in a manner consistent with elevated EE and lowered respiratory exchange ratio.
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Affiliation(s)
- Chaitanya K. Gavini
- School of Biomedical Sciences, Kent State University, Kent, Ohio, USA
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - Steven L. Britton
- Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Lauren G. Koch
- Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Colleen M. Novak
- School of Biomedical Sciences, Kent State University, Kent, Ohio, USA
- Department of Biological Sciences, Kent State University, Kent, Ohio, USA
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29
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Morselli LL, Claflin KE, Cui H, Grobe JL. Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin. Curr Hypertens Rep 2018; 20:25. [PMID: 29556733 DOI: 10.1007/s11906-018-0824-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Here, we review the current understanding of the functional neuroanatomy of neurons expressing Agouti-related peptide (AgRP) and the angiotensin 1A receptor (AT1A) within the arcuate nucleus (ARC) in the control of energy balance. RECENT FINDINGS The development and maintenance of obesity involves suppression of resting metabolic rate (RMR). RMR control is integrated via AgRP and proopiomelanocortin neurons within the ARC. Their projections to other hypothalamic and extrahypothalamic nuclei contribute to RMR control, though relatively little is known about the contributions of individual projections and the neurotransmitters involved. Recent studies highlight a role for AT1A, localized to AgRP neurons, but the specific function of AT1A within these cells remains unclear. AT1A functions within AgRP neurons to control RMR, but additional work is required to clarify its role within subpopulations of AgRP neurons projecting to distinct second-order nuclei, and the molecular mediators of its signaling within these cells.
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Affiliation(s)
- Lisa L Morselli
- Department of Pharmacology, University of Iowa, 51 Newton Rd., 2-307 BSB, Iowa City, IA, 52242, USA.,Department of Internal Medicine, Division of Endocrinology, University of Iowa, Iowa City, IA, 52242, USA
| | - Kristin E Claflin
- Department of Pharmacology, University of Iowa, 51 Newton Rd., 2-307 BSB, Iowa City, IA, 52242, USA
| | - Huxing Cui
- Department of Pharmacology, University of Iowa, 51 Newton Rd., 2-307 BSB, Iowa City, IA, 52242, USA.,Center for Hypertension Research, University of Iowa, Iowa City, IA, 52242, USA.,Obesity Research & Education Initiative, University of Iowa, Iowa City, IA, 52242, USA.,Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52242, USA.,Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, 52242, USA.,Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, 52242, USA
| | - Justin L Grobe
- Department of Pharmacology, University of Iowa, 51 Newton Rd., 2-307 BSB, Iowa City, IA, 52242, USA. .,Center for Hypertension Research, University of Iowa, Iowa City, IA, 52242, USA. .,Obesity Research & Education Initiative, University of Iowa, Iowa City, IA, 52242, USA. .,Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52242, USA. .,Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, 52242, USA. .,Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, 52242, USA.
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30
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Dore R, Levata L, Gachkar S, Jöhren O, Mittag J, Lehnert H, Schulz C. The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system. J Endocrinol 2017; 235:111-122. [PMID: 28851749 DOI: 10.1530/joe-17-0151] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 08/15/2017] [Indexed: 12/13/2022]
Abstract
Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.
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Affiliation(s)
- Riccardo Dore
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Luka Levata
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Sogol Gachkar
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Olaf Jöhren
- Center of BrainBehavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Jens Mittag
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Hendrik Lehnert
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Carla Schulz
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
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31
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What is "Hyper" in the ALS Hypermetabolism? Mediators Inflamm 2017; 2017:7821672. [PMID: 29081604 PMCID: PMC5610793 DOI: 10.1155/2017/7821672] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/03/2017] [Indexed: 12/11/2022] Open
Abstract
The progressive and fatal loss of upper (brain) and lower (spinal cord) motor neurons and muscle denervation concisely condenses the clinical picture of amyotrophic lateral sclerosis (ALS). Despite the multiple mechanisms believed to underlie the selective loss of motor neurons, ALS aetiology remains elusive and obscure. Likewise, there is also a cluster of alterations in ALS patients in which muscle wasting, body weight loss, eating dysfunction, and abnormal energy dissipation coexist. Defective energy metabolism characterizes the ALS progression, and such paradox of energy balance stands as a challenge for the understanding of ALS pathogenesis. The hypermetabolism in ALS will be examined from tissue-specific energy imbalance (e.g., skeletal muscle) to major energetic pathways (e.g., AMP-activated protein kinase) and whole-body energy alterations including glucose and lipid metabolism, nutrition, and potential involvement of interorgan communication. From the point of view here expressed, the hypermetabolism in ALS should be evaluated as a magnifying glass through which looking at the ALS pathogenesis is from a different perspective in which defective metabolism can disclose novel mechanistic interpretations and lines of intervention.
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Charlot K, Faure C, Antoine-Jonville S. Influence of Hot and Cold Environments on the Regulation of Energy Balance Following a Single Exercise Session: A Mini-Review. Nutrients 2017; 9:nu9060592. [PMID: 28604591 PMCID: PMC5490571 DOI: 10.3390/nu9060592] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 05/31/2017] [Accepted: 06/01/2017] [Indexed: 01/12/2023] Open
Abstract
Understanding the regulation of human food intake in response to an acute exercise session is of importance for interventions with athletes and soldiers, as well as overweight individuals. However, the influence of hot and cold environments on this crucial function for the regulation of body mass and motor performance has not been summarized. The purpose of this review was to exhaustively search the literature on the effect of ambient temperature during an exercise session on the subsequent subjective feeling of appetite, energy intake (EI) and its regulation. In the absence of stress due to environmental temperature, exercise-induced energy expenditure is not compensated by EI during an ad libitum meal following the session, probably due to decreased acylated ghrelin and increased peptide tyrosine tyrosine (PYY), glucagon-like peptide 1 (GLP-1), and pancreatic polypeptide (PP) levels. No systematic analysis has been yet made for major alterations of relative EI in cold and hot environments. However, observed eating behaviors are altered (proportion of solid/liquid food, carbohydrate/fat) and physiological regulation appears also to be altered. Anorexigenic signals, particularly PYY, appear to further increase in hot environments than in those that are thermoneutral. Ghrelin and leptin may be involved in the observed increase in EI after exercise in the cold, in parallel with increased energy expenditure. The potential influence of ambient thermal environment on eating behaviors after an exercise session should not be neglected.
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Affiliation(s)
- Keyne Charlot
- Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, 1 place Général Valérie André, BP 73, 91223 Brétigny-sur-Orge, France.
| | - Cécile Faure
- Laboratoire des Adaptations au Climat Tropical, Exercice et Santé, EA3596, Université des Antilles, Pointe-à-Pitre, BP 250, 97157 Pointe-à-Pitre CEDEX, Guadeloupe, France.
| | - Sophie Antoine-Jonville
- Laboratoire des Adaptations au Climat Tropical, Exercice et Santé, EA3596, Université des Antilles, Pointe-à-Pitre, BP 250, 97157 Pointe-à-Pitre CEDEX, Guadeloupe, France.
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Orellana JA, Cerpa W, Carvajal MF, Lerma-Cabrera JM, Karahanian E, Osorio-Fuentealba C, Quintanilla RA. New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis. Front Cell Neurosci 2017; 11:90. [PMID: 28424592 PMCID: PMC5380733 DOI: 10.3389/fncel.2017.00090] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 03/15/2017] [Indexed: 12/12/2022] Open
Abstract
Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood.
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Affiliation(s)
- Juan A Orellana
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Laboratorio de Neurociencias, Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de ChileSantiago, Chile
| | - Waldo Cerpa
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileSantiago, Chile
| | - Maria F Carvajal
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Unidad de Neurociencia, Centro de Investigación Biomédica, Universidad Autónoma de ChileSantiago, Chile
| | - José M Lerma-Cabrera
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Unidad de Neurociencia, Centro de Investigación Biomédica, Universidad Autónoma de ChileSantiago, Chile
| | - Eduardo Karahanian
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Unidad de Neurociencia, Centro de Investigación Biomédica, Universidad Autónoma de ChileSantiago, Chile
| | - Cesar Osorio-Fuentealba
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Facultad de Kinesiología, Artes y Educación Física, Universidad Metropolitana de Ciencias de la EducaciónSantiago, Chile
| | - Rodrigo A Quintanilla
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Laboratory of Neurodegenerative Diseases, Universidad Autónoma de ChileSantiago, Chile
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Almundarij TI, Gavini CK, Novak CM. Suppressed sympathetic outflow to skeletal muscle, muscle thermogenesis, and activity energy expenditure with calorie restriction. Physiol Rep 2017; 5:5/4/e13171. [PMID: 28242830 PMCID: PMC5328781 DOI: 10.14814/phy2.13171] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 01/29/2017] [Indexed: 12/21/2022] Open
Abstract
During weight loss, adaptive thermogenesis occurs where energy expenditure (EE) is suppressed beyond that predicted for the smaller body size. Here, we investigated the contributions of resting and nonresting EE to the reduced total EE seen after 3 weeks of 50% calorie restriction (CR) in rats, focusing on activity‐associated EE, muscle thermogenesis, and sympathetic outflow. Prolonged food restriction resulted in a 42% reduction in daily EE, through a 40% decrease in resting EE, and a 48% decline in nonresting EE. These decreases in EE were significant even when the reductions in body weight and lean mass were taken into account. Along with a decreased caloric need for low‐to‐moderate‐intensity treadmill activity with 50% CR, baseline and activity‐related muscle thermogenesis were also suppressed, though the ability to increase muscle thermogenesis above baseline levels was not compromised. When sympathetic drive was measured by assessing norepinephrine turnover (NETO), 50% CR was found to decrease NETO in three of the four muscle groups examined, whereas elevated NETO was found in white adipose tissue of food‐restricted rats. Central activation of melanocortin 4 receptors in the ventromedial hypothalamus stimulated this pathway, enhancing activity EE; this was not compromised by 50% CR. These data suggest that suppressed activity EE contributes to adaptive thermogenesis during energy restriction. This may stem from decreased sympathetic drive to skeletal muscle, increasing locomotor efficiency and reducing skeletal muscle thermogenesis. The capacity to increase activity EE in response to central stimuli is retained, however, presenting a potential target for preventing weight regain.
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Affiliation(s)
- Tariq I Almundarij
- College of Agriculture and Veterinary Medicine, Al Qassim University, Buraydah, Al-Qassim Province, Saudi Arabia.,Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Chaitanya K Gavini
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.,School of Biomedical Sciences, Kent State University, Kent, Ohio
| | - Colleen M Novak
- Department of Biological Sciences, Kent State University, Kent, Ohio .,School of Biomedical Sciences, Kent State University, Kent, Ohio
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35
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Minokoshi Y. Hypothalamic control of glucose and lipid metabolism in skeletal muscle. ACTA ACUST UNITED AC 2017. [DOI: 10.7600/jpfsm.6.75] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Yasuhiko Minokoshi
- Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences
- Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (Sokendai)
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36
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Almundarij TI, Smyers ME, Spriggs A, Heemstra LA, Beltz L, Dyne E, Ridenour C, Novak CM. Physical Activity, Energy Expenditure, and Defense of Body Weight in Melanocortin 4 Receptor-Deficient Male Rats. Sci Rep 2016; 6:37435. [PMID: 27886210 PMCID: PMC5122857 DOI: 10.1038/srep37435] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/28/2016] [Indexed: 01/28/2023] Open
Abstract
Melanocortin 4 receptor (MC4R) variants contribute to human obesity, and rats lacking functional MC4R (Mc4rK314X/K314X) are obese. We investigated the hypothesis that low energy expenditure (EE) and physical activity contribute to this obese phenotype in male rats, and determined whether lack of functional MC4R conferred protection from weight loss during 50% calorie restriction. Though Mc4rK314X/K314X rats showed low brown adipose Ucp1 expression and were less physically active than rats heterozygous for the mutation (Mc4r+/K314X) or wild-type (Mc4r+/+) rats, we found no evidence of lowered EE in Mc4rK314X/K314X rats once body weight was taken into account using covariance. Mc4rK314X/K314X rats had a significantly higher respiratory exchange ratio. Compared to Mc4r+/+ rats, Mc4rK314X/K314X and Mc4r+/K314X rats lost less lean mass during calorie restriction, and less body mass when baseline weight was accounted for. Limited regional overexpression of Mc3r was found in the hypothalamus. Although lower physical activity levels in rats with nonfunctional MC4R did not result in lower total EE during free-fed conditions, rats lacking one or two functional copies of Mc4r showed conservation of mass, particularly lean mass, during energy restriction. This suggests that variants affecting MC4R function may contribute to individual differences in the metabolic response to food restriction.
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Affiliation(s)
- Tariq I Almundarij
- College of Agriculture and Veterinary Medicine, Al-Qassim University, Buraydah, Al-Qassim Province, Saudi Arabia.,Department of Biological Sciences, Kent State University, Kent, OH, 44242, US
| | - Mark E Smyers
- School of Biomedical Sciences, Kent State University, Kent, OH, 44242, US
| | - Addison Spriggs
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, US
| | - Lydia A Heemstra
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, US
| | - Lisa Beltz
- Department of Natural Sciences, Malone University, Canton, OH, 44709, US
| | - Eric Dyne
- School of Biomedical Sciences, Kent State University, Kent, OH, 44242, US.,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, US
| | - Caitlyn Ridenour
- Department of Natural Sciences, Malone University, Canton, OH, 44709, US
| | - Colleen M Novak
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, US.,School of Biomedical Sciences, Kent State University, Kent, OH, 44242, US
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37
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Dunn J, Mittendorfer B. How the brain tips the scale. J Physiol 2016; 594:5041-2. [PMID: 27629075 DOI: 10.1113/jp272701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Affiliation(s)
- Julia Dunn
- VA St Louis Health Care System, St Louis, MO, 63110, USA.,Center for Human Nutrition and Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA
| | - Bettina Mittendorfer
- Center for Human Nutrition and Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA.
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