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Gillette R, Turnbull IC, Nair VD, Gaitas A. Preliminary Insights into the Acute Molecular Responses in C2C12 Myotubes to Hyperthermia and Insulin Treatment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.26.644592. [PMID: 40196696 PMCID: PMC11974855 DOI: 10.1101/2025.03.26.644592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
This study investigates the differential gene expression in an immortalized cell line of mouse skeletal myoblasts (C2C12)-derived myotube cells subjected to hyperthermia (40°C) with and without insulin treatment to elucidate the impact of thermal stress on skeletal muscle physiology. Hyperthermia, which occurs during intense physical activity or environmental heat exposure, is known to challenge muscle homeostasis and influence metabolic function. mRNA sequencing revealed that hyperthermia robustly altered gene expression-upregulating key genes involved in glycolysis, oxidative phosphorylation, heat shock response, and apoptosis. These changes are suggestive of an elevated metabolic state and enhanced cellular stress; however, these results remain preliminary without complementary protein or metabolic assays. Notably, insulin treatment moderated many of the hyperthermia-induced transcriptional alterations, particularly affecting genes linked to glucose uptake and metabolism. Together, these findings provide hypothesis-generating insights into the interplay between thermal stress and insulin signaling in C2C12 myotubes, and they underscore potential targets for future mechanistic studies.
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Affiliation(s)
- Ross Gillette
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Irene C. Turnbull
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Venugopalan D. Nair
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Angelo Gaitas
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- BioMedical Engineering & Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Salazar-Hernández E, Bahena-Cuevas OE, Mendoza-Bello JM, Barragán-Bonilla MI, Sánchez-Alavez M, Espinoza-Rojo M. Relationship Between Brain Insulin Resistance, Carbohydrate Consumption, and Protein Carbonyls, and the Link Between Peripheral Insulin Resistance, Fat Consumption, and Malondialdehyde. Biomedicines 2025; 13:404. [PMID: 40002817 PMCID: PMC11853321 DOI: 10.3390/biomedicines13020404] [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: 01/03/2025] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
The consumption of a high-fat (HFD) or high-carbohydrate/low-fat (LFD) diet is related to insulin resistance; however, central and peripheral alterations can occur independently. In this study, the timeline of insulin resistance was determined while taking into consideration the role of diet in oxidative damage. Background/Objectives: The aim of this study was to ascertain whether a HFD or LFD induces peripheral insulin resistance (PIR) before brain insulin resistance (BIR), and whether the timing of these alterations correlates with heightened oxidative damage markers in plasma, adipose tissue, and the cerebral cortex. Methodology and Results: Three-month-old C57BL/6 male mice were fed with a HFD, LFD, or standard diet for 1, 2, or 3 months. Glucose and insulin tolerance tests were performed to determine PIR, and the hypothalamic thermogenic response to insulin was used to determine their BIR status. For oxidative damage, the levels of malondialdehyde (MDA) and the protein carbonyl group (PCO) and the enzymatic activity of glutathione peroxidase (GSH-Px) were evaluated in plasma, white adipose tissue, brown adipose tissue, and the cerebral cortex. PIR occurred at 3 months of the HFD, but MDA levels in the white adipose tissue increased at 2 months. BIR occurred at 1 and 2 months of the LFD, but the enzymatic activity of GSH-Px was lower at 1 month and the amount of the PCO increased at 2 months. Conclusions: The intake of a HFD or LFD of different durations can influence the establishment of PIR or BIR, and oxidative damage in the fat tissue and cerebral cortex can play an important role.
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Affiliation(s)
- Elena Salazar-Hernández
- Laboratory of Molecular Biology and Genomic, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo 39090, Guerrero, Mexico; (E.S.-H.); (O.E.B.-C.); (J.M.M.-B.); (M.I.B.-B.)
| | - Oscar Ezequiel Bahena-Cuevas
- Laboratory of Molecular Biology and Genomic, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo 39090, Guerrero, Mexico; (E.S.-H.); (O.E.B.-C.); (J.M.M.-B.); (M.I.B.-B.)
| | - Juan Miguel Mendoza-Bello
- Laboratory of Molecular Biology and Genomic, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo 39090, Guerrero, Mexico; (E.S.-H.); (O.E.B.-C.); (J.M.M.-B.); (M.I.B.-B.)
| | - Martha Isela Barragán-Bonilla
- Laboratory of Molecular Biology and Genomic, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo 39090, Guerrero, Mexico; (E.S.-H.); (O.E.B.-C.); (J.M.M.-B.); (M.I.B.-B.)
| | - Manuel Sánchez-Alavez
- Faculty of Medicine and Psychology, Autonomous University of Baja California, Tijuana 22390, Baja California, Mexico;
| | - Mónica Espinoza-Rojo
- Laboratory of Molecular Biology and Genomic, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo 39090, Guerrero, Mexico; (E.S.-H.); (O.E.B.-C.); (J.M.M.-B.); (M.I.B.-B.)
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Peng Y, Yao SY, Chen Q, Jin H, Du MQ, Xue YH, Liu S. True or false? Alzheimer's disease is type 3 diabetes: Evidences from bench to bedside. Ageing Res Rev 2024; 99:102383. [PMID: 38955264 DOI: 10.1016/j.arr.2024.102383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 07/04/2024]
Abstract
Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aβ, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.
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Affiliation(s)
- Yong Peng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China.
| | - Shun-Yu Yao
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Quan Chen
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Hong Jin
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Miao-Qiao Du
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Ya-Hui Xue
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Shu Liu
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
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Perlman RF, Beehner JC, Koenig A, Lu A. Consumption of underground storage organs is associated with improved energetic status in a graminivorous primate. J Hum Evol 2024; 192:103545. [PMID: 38843698 DOI: 10.1016/j.jhevol.2024.103545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 04/07/2024] [Accepted: 04/14/2024] [Indexed: 06/23/2024]
Abstract
Early hominin species likely had access to open, grassy habitats where periodic reliance on underground storage organs (USOs) is hypothesized to have played a crucial dietary role. As the only living graminivorous primate today, geladas (Theropithecus gelada) provide a unique perspective for understanding the energetic consequences of seasonal consumption of USOs. Geladas rely heavily on above-ground grasses throughout the year, but when grass is seasonally less available, they feed more on USOs. To assess whether USOs fit the definition of fallback foods (i.e., foods that are difficult to access, less preferred, or both), we examined how foraging effort (measured via time spent feeding and moving) and energetic status (measured via urinary C-peptide) fluctuated during seasonal dietary changes in a population of wild geladas in the Simien Mountains National Park, Ethiopia. If, indeed, USOs are fallback foods, we predicted an increase in foraging effort and a decline in energetic status during the dry season, when geladas rely more heavily on USOs. We collected behavioral and physiological data from 13 adult gelada males across a 13-month period. As expected, we found that male geladas spent more time moving during drier months. However, counter to the hypothesis that USOs are fallback foods in geladas, urinary C-peptide concentrations were significantly higher during the dry season. We suggest that USOs may represent an energy-rich food item for geladas, but it remains unclear why USOs are not consumed year-round. Future work is needed to better understand seasonal variation in the availability, nutrient content, and digestibility of USOs. However, results indicate that exploiting USOs seasonally could have been a valuable dietary strategy for the evolutionary success of early hominins.
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Affiliation(s)
- Rachel F Perlman
- Interdepartmental Doctoral Program in Anthropological Sciences, Stony Brook University, Stony Brook, NY 11794-4364, USA; Program for Research Initiatives in Science & Math, John Jay College of Criminal Justice, City University of New York, New York, NY 10019, USA.
| | - Jacinta C Beehner
- Department of Psychology, University of Michigan, Ann Arbor, MI 48109-1043, USA; Department of Anthropology, University of Michigan, Ann Arbor, MI 48109-1107, USA
| | - Andreas Koenig
- Interdepartmental Doctoral Program in Anthropological Sciences, Stony Brook University, Stony Brook, NY 11794-4364, USA; Department of Anthropology, Stony Brook University, Stony Brook, NY 11794-4364, USA
| | - Amy Lu
- Interdepartmental Doctoral Program in Anthropological Sciences, Stony Brook University, Stony Brook, NY 11794-4364, USA; Department of Anthropology, Stony Brook University, Stony Brook, NY 11794-4364, USA.
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Wee J, Tan XR, Gunther SH, Ihsan M, Leow MKS, Tan DSY, Eriksson JG, Lee JKW. Effects of Medications on Heat Loss Capacity in Chronic Disease Patients: Health Implications Amidst Global Warming. Pharmacol Rev 2023; 75:1140-1166. [PMID: 37328294 DOI: 10.1124/pharmrev.122.000782] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 04/20/2023] [Accepted: 05/31/2023] [Indexed: 06/18/2023] Open
Abstract
Pharmacological agents used to treat or manage diseases can modify the level of heat strain experienced by chronically ill and elderly patients via different mechanistic pathways. Human thermoregulation is a crucial homeostatic process that maintains body temperature within a narrow range during heat stress through dry (i.e., increasing skin blood flow) and evaporative (i.e., sweating) heat loss, as well as active inhibition of thermogenesis, which is crucial to avoid overheating. Medications can independently and synergistically interact with aging and chronic disease to alter homeostatic responses to rising body temperature during heat stress. This review focuses on the physiologic changes, with specific emphasis on thermolytic processes, associated with medication use during heat stress. The review begins by providing readers with a background of the global chronic disease burden. Human thermoregulation and aging effects are then summarized to give an understanding of the unique physiologic changes faced by older adults. The effects of common chronic diseases on temperature regulation are outlined in the main sections. Physiologic impacts of common medications used to treat these diseases are reviewed in detail, with emphasis on the mechanisms by which these medications alter thermolysis during heat stress. The review concludes by providing perspectives on the need to understand the effects of medication use in hot environments, as well as a summary table of all clinical considerations and research needs of the medications included in this review. SIGNIFICANCE STATEMENT: Long-term medications modulate thermoregulatory function, resulting in excess physiological strain and predisposing patients to adverse health outcomes during prolonged exposures to extreme heat during rest and physical work (e.g., exercise). Understanding the medication-specific mechanisms of altered thermoregulation has importance in both clinical and research settings, paving the way for work toward refining current medication prescription recommendations and formulating mitigation strategies for adverse drug effects in the heat in chronically ill patients.
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Affiliation(s)
- Jericho Wee
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Xiang Ren Tan
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Samuel H Gunther
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Mohammed Ihsan
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Melvin Khee Shing Leow
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Doreen Su-Yin Tan
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Johan G Eriksson
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
| | - Jason Kai Wei Lee
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (J.W., X.R.T., S.H.G., M.I., M.K.S.L., J.G.E., J.K.W.L.), Department of Pharmacy, Faculty of Science, (D.S.-Y.T), Department of Physiology, Yong Loo Lin School of Medicine (J.K.W.L.), Heat Resilience and Performance Centre, Yong Loo Lin School of Medicine (J.K.W.L.), National University of Singapore, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore (X.R.T.); Campus for Research Excellence and Technological Enterprise, Singapore (S.H.G., J.K.W.L.); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (M.K.S.L.); Duke-National University of Singapore Medical School, Singapore (M.K.S.L.); Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore (M.K.S.L.); Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (M.K.S.L., J.G.E.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, University of Helsinki, Helsinki, Finland (J.G.E.); and Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (J.G.E.)
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Chiang MH, Lin YC, Chen SF, Lee PS, Fu TF, Wu T, Wu CL. Independent insulin signaling modulators govern hot avoidance under different feeding states. PLoS Biol 2023; 21:e3002332. [PMID: 37847673 PMCID: PMC10581474 DOI: 10.1371/journal.pbio.3002332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
Thermosensation is critical for the survival of animals. However, mechanisms through which nutritional status modulates thermosensation remain unclear. Herein, we showed that hungry Drosophila exhibit a strong hot avoidance behavior (HAB) compared to food-sated flies. We identified that hot stimulus increases the activity of α'β' mushroom body neurons (MBns), with weak activity in the sated state and strong activity in the hungry state. Furthermore, we showed that α'β' MBn receives the same level of hot input from the mALT projection neurons via cholinergic transmission in sated and hungry states. Differences in α'β' MBn activity between food-sated and hungry flies following heat stimuli are regulated by distinct Drosophila insulin-like peptides (Dilps). Dilp2 is secreted by insulin-producing cells (IPCs) and regulates HAB during satiety, whereas Dilp6 is secreted by the fat body and regulates HAB during the hungry state. We observed that Dilp2 induces PI3K/AKT signaling, whereas Dilp6 induces Ras/ERK signaling in α'β' MBn to regulate HAB in different feeding conditions. Finally, we showed that the 2 α'β'-related MB output neurons (MBONs), MBON-α'3 and MBON-β'1, are necessary for the output of integrated hot avoidance information from α'β' MBn. Our results demonstrate the presence of dual insulin modulation pathways in α'β' MBn, which are important for suitable behavioral responses in Drosophila during thermoregulation under different feeding states.
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Affiliation(s)
- Meng-Hsuan Chiang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Chun Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Sheng-Fu Chen
- NHRI Institute of Biomedical Engineering & Nanomedicine, Miaoli, Taiwan
| | - Peng-Shiuan Lee
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tsai-Feng Fu
- Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan
| | - Tony Wu
- Department of Neurology, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital, New Taipei City, Taiwan
| | - Chia-Lin Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Neurology, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan
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Grant AD, Kriegsfeld LJ. Neural substrates underlying rhythmic coupling of female reproductive and thermoregulatory circuits. Front Physiol 2023; 14:1254287. [PMID: 37753455 PMCID: PMC10518419 DOI: 10.3389/fphys.2023.1254287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/30/2023] [Indexed: 09/28/2023] Open
Abstract
Coordinated fluctuations in female reproductive physiology and thermoregulatory output have been reported for over a century. These changes occur rhythmically at the hourly (ultradian), daily (circadian), and multi-day (ovulatory) timescales, are critical for reproductive function, and have led to the use of temperature patterns as a proxy for female reproductive state. The mechanisms underlying coupling between reproductive and thermoregulatory systems are not fully established, hindering the expansion of inferences that body temperature can provide about female reproductive status. At present, numerous digital tools rely on temperature to infer the timing of ovulation and additional applications (e.g., monitoring ovulatory irregularities and progression of puberty, pregnancy, and menopause are developed based on the assumption that reproductive-thermoregulatory coupling occurs across timescales and life stages. However, without clear understanding of the mechanisms and degree of coupling among the neural substrates regulating temperature and the reproductive axis, whether such approaches will bear fruit in particular domains is uncertain. In this overview, we present evidence supporting broad coupling among the central circuits governing reproduction, thermoregulation, and broader systemic physiology, focusing on timing at ultradian frequencies. Future work characterizing the dynamics of reproductive-thermoregulatory coupling across the lifespan, and of conditions that may decouple these circuits (e.g., circadian disruption, metabolic disease) and compromise female reproductive health, will aid in the development of strategies for early detection of reproductive irregularities and monitoring the efficacy of fertility treatments.
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Affiliation(s)
| | - Lance J. Kriegsfeld
- Department of Psychology, University of California, Berkeley, CA, United States
- The Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States
- Department of Integrative Biology, University of California, Berkeley, CA, United States
- Graduate Group in Endocrinology, University of California, Berkeley, CA, United States
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De la Cruz-Concepción B, Flores-Cortez YA, Barragán-Bonilla MI, Mendoza-Bello JM, Espinoza-Rojo M. Insulin: A connection between pancreatic β cells and the hypothalamus. World J Diabetes 2023; 14:76-91. [PMID: 36926659 PMCID: PMC10011898 DOI: 10.4239/wjd.v14.i2.76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/13/2022] [Accepted: 01/17/2023] [Indexed: 02/14/2023] Open
Abstract
Insulin is a hormone secreted by pancreatic β cells. The concentration of glucose in circulation is proportional to the secretion of insulin by these cells. In target cells, insulin binds to its receptors and activates phosphatidylinositol-3-kinase/protein kinase B, inducing different mechanisms depending on the cell type. In the liver it activates the synthesis of glycogen, in adipose tissue and muscle it allows the capture of glucose, and in the hypothalamus, it regulates thermogenesis and appetite. Defects in insulin function [insulin resistance (IR)] are related to the development of neurodegenerative diseases in obese people. Furthermore, in obesity and diabetes, its role as an anorexigenic hormone in the hypothalamus is diminished during IR. Therefore, hyperphagia prevails, which aggravates hyper-glycemia and IR further, becoming a vicious circle in which the patient cannot regulate their need to eat. Uncontrolled calorie intake induces an increase in reactive oxygen species, overcoming cellular antioxidant defenses (oxidative stress). Reactive oxygen species activate stress-sensitive kinases, such as c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that induce phos-phorylation in serine residues in the insulin receptor, which blocks the insulin signaling pathway, continuing the mechanism of IR. The brain and pancreas are organs mainly affected by oxidative stress. The use of drugs that regulate food intake and improve glucose metabolism is the conventional therapy to improve the quality of life of these patients. Currently, the use of antioxidants that regulate oxidative stress has given good results because they reduce oxidative stress and inflammatory processes, and they also have fewer side effects than synthetic drugs.
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Affiliation(s)
- Brenda De la Cruz-Concepción
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Yaccil Adilene Flores-Cortez
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Martha Isela Barragán-Bonilla
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Juan Miguel Mendoza-Bello
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Monica Espinoza-Rojo
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
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9
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Stewart J, Arneson A, Byrd M, Negron-Perez V, Newberne H, White R, El-Kadi S, Ealy A, Rhoads R, Rhoads M. Comparison of production-related responses to hyperinsulinemia and hypoglycemia induced by clamp procedures or heat stress of lactating dairy cattle. J Dairy Sci 2022; 105:8439-8453. [DOI: 10.3168/jds.2022-21922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/12/2022] [Indexed: 11/19/2022]
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10
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Grant AD, Wilbrecht L, Kriegsfeld LJ. Sex Differences in Pubertal Circadian and Ultradian Rhythmic Development Under Semi-naturalistic Conditions. J Biol Rhythms 2022; 37:442-454. [PMID: 35502708 PMCID: PMC9329191 DOI: 10.1177/07487304221092715] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Biological rhythms in core body temperature (CBT) provide informative markers of adolescent development under controlled laboratory conditions. However, it is unknown whether these markers are preserved under more variable, semi-naturalistic conditions, and whether CBT may therefore prove useful in a real-world setting. To evaluate this possibility, we examined fecal steroid concentrations and CBT rhythms from pre-adolescence (p26) through early adulthood (p76) in intact male and female Wistar rats under natural light and climate at the Stephen Glickman Field Station for the Study of Behavior, Ecology and Reproduction. Despite greater environmental variability, CBT markers of pubertal onset and its rhythmic progression were comparable with those previously reported in laboratory conditions in female rats and extend actigraphy-based findings in males. Specifically, sex differences emerged in CBT circadian rhythm (CR) power and amplitude prior to pubertal onset and persisted into early adulthood, with females exhibiting elevated CBT and decreased CR power compared with males. Within-day (ultradian rhythm [UR]) patterns also exhibited a pronounced sex difference associated with estrous cyclicity. Pubertal onset, defined by vaginal opening, preputial separation, and sex steroid concentrations, occurred later than previously reported under lab conditions for both sexes. Vaginal opening and increased fecal estradiol concentrations were closely tied to the commencement of 4-day oscillations in CBT and UR power. By contrast, preputial separation and the first rise in testosterone concentration were not associated with adolescent changes to CBT rhythms in male rats. Together, males and females exhibited unique temporal patterning of CBT and sex steroids across pubertal development, with tractable associations between hormonal concentrations, external development, and temporal structure in females. The preservation of these features outside the laboratory supports CBT as a strong candidate for translational pubertal monitoring under semi-naturalistic conditions in females.
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Affiliation(s)
- Azure D. Grant
- The Helen Wills Neuroscience Institute, University of California, Berkeley, CA, 94720, United States
| | - Linda Wilbrecht
- The Helen Wills Neuroscience Institute, University of California, Berkeley, CA, 94720, United States
- Department of Psychology, University of California, Berkeley, CA, 94720, United States
| | - Lance J. Kriegsfeld
- The Helen Wills Neuroscience Institute, University of California, Berkeley, CA, 94720, United States
- Department of Psychology, University of California, Berkeley, CA, 94720, United States
- Department of Integrative Biology, University of California, Berkeley, CA, 94720, United States
- Graduate Group in Endocrinology, University of California, Berkeley, CA, 94720, United States
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11
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Grant AD, Wilbrecht L, Kriegsfeld LJ. Adolescent Development of Biological Rhythms in Female Rats: Estradiol Dependence and Effects of Combined Contraceptives. Front Physiol 2021; 12:752363. [PMID: 35615288 PMCID: PMC9126190 DOI: 10.3389/fphys.2021.752363] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/11/2021] [Indexed: 01/23/2023] Open
Abstract
Adolescence is a period of continuous development, including the maturation of endogenous rhythms across systems and timescales. Although, these dynamic changes are well-recognized, their continuous structure and hormonal dependence have not been systematically characterized. Given the well-established link between core body temperature (CBT) and reproductive hormones in adults, we hypothesized that high-resolution CBT can be applied to passively monitor pubertal development and disruption with high fidelity. To examine this possibility, we used signal processing to investigate the trajectory of CBT rhythms at the within-day (ultradian), daily (circadian), and ovulatory timescales, their dependence on estradiol (E2), and the effects of hormonal contraceptives. Puberty onset was marked by a rise in fecal estradiol (fE2), followed by an elevation in CBT and circadian power. This time period marked the commencement of 4-day rhythmicity in fE2, CBT, and ultradian power marking the onset of the estrous cycle. The rise in circadian amplitude was accelerated by E2 treatment, indicating a role for this hormone in rhythmic development. Contraceptive administration in later adolescence reduced CBT and circadian power and resulted in disruption to 4-day cycles that persisted after discontinuation. Our data reveal with precise temporal resolution how biological rhythms change across adolescence and demonstrate a role for E2 in the emergence and preservation of multiscale rhythmicity. These findings also demonstrate how hormones delivered exogenously in a non-rhythmic pattern can disrupt rhythmic development. These data lay the groundwork for a future in which temperature metrics provide an inexpensive, convenient method for monitoring pubertal maturation and support the development of hormone therapies that better mimic and support human chronobiology.
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Affiliation(s)
- Azure D. Grant
- The Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, United States
| | - Linda Wilbrecht
- The Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, United States
- Department of Psychology, University of California, Berkeley, Berkeley, CA, United States
| | - Lance J. Kriegsfeld
- The Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, United States
- Department of Psychology, University of California, Berkeley, Berkeley, CA, United States
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, United States
- Graduate Group in Endocrinology, University of California, Berkeley, Berkeley, CA, United States
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12
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Scherer T, Sakamoto K, Buettner C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 2021; 17:468-483. [PMID: 34108679 DOI: 10.1038/s41574-021-00498-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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13
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Martins MG, Cruz AGD, Oliveira GPD, Woodside B, Horta-Júnior JDADCE, Kiss ACI. Effects of snack intake during pregnancy and lactation on reproductive outcome in mild hyperglycemic rats. Physiol Behav 2021; 240:113544. [PMID: 34332976 DOI: 10.1016/j.physbeh.2021.113544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 11/17/2022]
Abstract
Metabolic disorders, like diabetes, as well as maternal diet, alter nutrient availability in utero, inducing adaptations in the offspring. Whether the effects of maternal hyperglycemia are modulated by diet, however, has yet to be explored. In the current study, we examined this issue by giving females rats, treated neonatally with STZ to induce mild hyperglycemia, and control littermates either ad libitum access to standard chow (Control n = 17; STZ n = 16) or standard chow and snacks (Control-snack n = 18; STZ-snack n = 19) (potato chips and a red fruit-flavored sucrose syrup solution 1.5%) throughout pregnancy and lactation. We hypothesized that the maternal glucose intolerance typically seen in female rats treated neonatally with STZ would be exacerbated by snack intake, and that the combination of snack intake and STZ treatment would lead to alterations in maternal behavior and offspring development. Maternal body weight and food intake were measured daily through pregnancy and lactation and litter weight throughout lactation. At birth, litter size, offspring weight, body length, and anogenital distance were obtained and offspring were classified according to their weight. Measures of nursing and retrieval behavior, as well as exploration in the open field and the elevated plus-maze were also recorded. As predicted, snack intake tended to aggravate the glucose intolerance of STZ-treated rats during pregnancy. Both Control and STZ-treated females that had access to snacks ate more calories and fat, but less carbohydrate and protein than females having access to chow alone. Overall, STZ-treated dams gave birth to fewer pups. Chow-fed STZ females gave birth to a greater proportion of large for pregnancy age pups, whereas dams in the Control-snack group gave birth to a greater proportion of small pups. The birth weight classification of pups born to STZ-snack rats, however, resembled that of the Control chow-fed females. Although all litters gained weight during lactation, litters from snack-fed dams gained less weight regardless of maternal hyperglycemia and did not show catch-up growth by weaning. Overall, STZ rats spent more time nest building, whereas the average inter milk ejection interval was higher in snack-fed females. STZ-snack dams retrieved the complete litter faster than dams in the other groups. Together, these data suggest that when mild hyperglycemic females are given access to snacks throughout pregnancy and lactation their intake is similar to that of Control females given snack access. The combination of hyperglycemia and snack access tended to decrease glucose tolerance in pregnancy, and normalized birth weight classification, but produced few other effects that were not seen as a function of snack intake or hyperglycemia alone. Since birth weight is a strong predictor of health issues, future studies will further investigate offspring behavioral and metabolic outcomes later in life.
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Affiliation(s)
- Marina Galleazzo Martins
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil.
| | - Alessandra Gonçalves da Cruz
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| | - Giovana Pereira de Oliveira
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| | - Barbara Woodside
- Center for Studies in Behavioral Neurobiology, Psychology Department, Concordia University, 7141 Sherbrooke St. W., Montreal, Quebec, Canada H4B 1R6
| | - José de Anchieta de Castro E Horta-Júnior
- São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| | - Ana Carolina Inhasz Kiss
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
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Bahari F, Yavari M. Hot and Cold Theory: Evidence in Systems Biology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1343:135-160. [DOI: 10.1007/978-3-030-80983-6_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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15
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Manaserh IH, Maly E, Jahromi M, Chikkamenahalli L, Park J, Hill J. Insulin sensing by astrocytes is critical for normal thermogenesis and body temperature regulation. J Endocrinol 2020; 247:39-52. [PMID: 32698146 PMCID: PMC7456332 DOI: 10.1530/joe-20-0052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022]
Abstract
The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.
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Affiliation(s)
- Iyad H Manaserh
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
| | - Emily Maly
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
| | - Marziyeh Jahromi
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
| | - Lakshmikanth Chikkamenahalli
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
| | - Joshua Park
- Department of Neuroscience, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
| | - Jennifer Hill
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, USA
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16
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Siemienowicz K, Rae MT, Howells F, Anderson C, Nicol LM, Franks S, Duncan WC. Insights into Manipulating Postprandial Energy Expenditure to Manage Weight Gain in Polycystic Ovary Syndrome. iScience 2020; 23:101164. [PMID: 32464593 PMCID: PMC7256642 DOI: 10.1016/j.isci.2020.101164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 04/08/2020] [Accepted: 05/11/2020] [Indexed: 11/30/2022] Open
Abstract
Women with polycystic ovary syndrome (PCOS) are more likely to be obese and have difficulty in losing weight. They demonstrate an obesity-independent deficit in adaptive energy expenditure. We used a clinically realistic preclinical model to investigate the molecular basis for the reduced postprandial thermogenesis (PPT) and develop a therapeutic strategy to normalize this deficit. Sheep exposed to increased androgens before birth develop the clinical features of PCOS. In adulthood they develop obesity and demonstrate an obesity-independent reduction in PPT. This is associated with reduced adipose tissue uncoupling protein expression and adipose tissue noradrenaline concentrations. These sheep are insulin resistant with reduced insulin signaling in the brain. Increasing brain insulin concentrations using intranasal insulin administration increased PPT in PCOS sheep without any effects on blood glucose concentrations. Intranasal insulin administration with food is a potential novel strategy to improve adaptive energy expenditure and normalize the responses to weight loss strategies in women with PCOS.
Obesity can be prenatally programmed by androgens in an ovine model of PCOS This model has the same deficit in postprandial energy expenditure as women with PCOS Reduced adipose tissue thermogenesis links to lower central insulin signaling Therapeutic intranasal insulin raises postprandial energy expenditure in PCOS sheep
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Affiliation(s)
- Katarzyna Siemienowicz
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK; School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK
| | - Michael T Rae
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK
| | - Fiona Howells
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Chloe Anderson
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Linda M Nicol
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Stephen Franks
- Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK
| | - William C Duncan
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
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17
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Tabarean IV. Neurotensin induces hypothermia by activating both neuronal neurotensin receptor 1 and astrocytic neurotensin receptor 2 in the median preoptic nucleus. Neuropharmacology 2020; 171:108069. [PMID: 32275927 DOI: 10.1016/j.neuropharm.2020.108069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/20/2020] [Accepted: 03/22/2020] [Indexed: 12/13/2022]
Abstract
Neurotensin (NTS) is a neuropeptide acting as a neuromodulator in the brain and is a very potent hypothermic agent. However, the cellular mechanisms of actions are not fully understood. Here we report that NTS increases the firing rate of preoptic GABAergic neurons by activating both neurotensin receptor 1 (NTSR1) and neurotensin receptor 2 (NTSR2), expressed by neurons and astrocytes, respectively. Downstream of NTSR1 the neuropeptide activated an inward current, calcium release from intracellular stores and, postsynaptically, increased frequency and amplitude of inhibitory synaptic events. NTSR2 activation in astrocytes resulted in increased excitatory input in preoptic GABAergic neurons, an effect which was dependent upon the activation of P2X4 receptors. We also found that neuromedin N acted as a selective agonist at the NTSR1. Surprisingly, activation of both NTSR1 and NTSR2 in the median preoptic nucleus was required for activating a full hypothermic response.
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Affiliation(s)
- Iustin V Tabarean
- Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, 92121, CA, USA.
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18
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Samodien E, Pheiffer C, Erasmus M, Mabasa L, Louw J, Johnson R. Diet-induced DNA methylation within the hypothalamic arcuate nucleus and dysregulated leptin and insulin signaling in the pathophysiology of obesity. Food Sci Nutr 2019; 7:3131-3145. [PMID: 31660128 PMCID: PMC6804761 DOI: 10.1002/fsn3.1169] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/18/2019] [Accepted: 07/24/2019] [Indexed: 12/24/2022] Open
Abstract
Obesity rates continue to rise in an unprecedented manner in what could be the most rapid population‐scale shift in human phenotype ever to occur. Increased consumption of unhealthy, calorie‐dense foods, coupled with sedentary lifestyles, is the main factor contributing to a positive energy balance and the development of obesity. Leptin and insulin are key hormones implicated in pathogenesis of this disorder and are crucial for controlling whole‐body energy homeostasis. Their respective function is mediated by the counterbalance of anorexigenic and orexigenic neurons located within the hypothalamic arcuate nucleus. Dysregulation of leptin and insulin signaling pathways within this brain region may contribute not only to the development of obesity, but also systemically affect the peripheral organs, thereby manifesting as metabolic diseases. Although the exact mechanisms detailing how these hypothalamic nuclei contribute to disease pathology are still unclear, increasing evidence suggests that altered DNA methylation may be involved. This review evaluates animal studies that have demonstrated diet‐induced DNA methylation changes in genes that regulate energy homeostasis within the arcuate nucleus, and elucidates possible mechanisms causing hypothalamic leptin and insulin resistance leading to the development of obesity and metabolic diseases.
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Affiliation(s)
- Ebrahim Samodien
- Biomedical Research and Innovation Platform South African Medical Research Council. Tygerberg Cape Town South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform South African Medical Research Council. Tygerberg Cape Town South Africa.,Department of Medical Physiology Stellenbosch University Tygerberg South Africa
| | - Melisse Erasmus
- Biomedical Research and Innovation Platform South African Medical Research Council. Tygerberg Cape Town South Africa.,Department of Medical Physiology Stellenbosch University Tygerberg South Africa
| | - Lawrence Mabasa
- Biomedical Research and Innovation Platform South African Medical Research Council. Tygerberg Cape Town South Africa
| | - Johan Louw
- Biomedical Research and Innovation Platform South African Medical Research Council. Tygerberg Cape Town South Africa.,Department of Biochemistry and Microbiology University of Zululand KwaDlangezwa South Africa
| | - Rabia Johnson
- Biomedical Research and Innovation Platform South African Medical Research Council. Tygerberg Cape Town South Africa.,Department of Medical Physiology Stellenbosch University Tygerberg South Africa
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19
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Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci U S A 2019; 116:6379-6384. [PMID: 30765523 DOI: 10.1073/pnas.1817391116] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Previous studies have shown that insulin and IGF-1 signaling in the brain, especially the hypothalamus, is important for regulation of systemic metabolism. Here, we develop mice in which we have specifically inactivated both insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) in the hippocampus (Hippo-DKO) or central amygdala (CeA-DKO) by stereotaxic delivery of AAV-Cre into IRlox/lox/IGF1Rlox/lox mice. Consequently, both Hippo-DKO and CeA-DKO mice have decreased levels of the GluA1 subunit of glutamate AMPA receptor and display increased anxiety-like behavior, impaired cognition, and metabolic abnormalities, including glucose intolerance. Hippo-DKO mice also display abnormal spatial learning and memory whereas CeA-DKO mice have impaired cold-induced thermogenesis. Thus, insulin/IGF-1 signaling has common roles in the hippocampus and central amygdala, affecting synaptic function, systemic glucose homeostasis, behavior, and cognition. In addition, in the hippocampus, insulin/IGF-1 signaling is important for spatial learning and memory whereas insulin/IGF-1 signaling in the central amygdala controls thermogenesis via regulation of neural circuits innervating interscapular brown adipose tissue.
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Bastardot F, Marques-Vidal P, Vollenweider P. Association of body temperature with obesity. The CoLaus study. Int J Obes (Lond) 2018; 43:1026-1033. [PMID: 30250242 PMCID: PMC6760582 DOI: 10.1038/s41366-018-0218-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 08/09/2018] [Accepted: 08/29/2018] [Indexed: 12/19/2022]
Abstract
Background and aims There is conflicting evidence regarding the association between body temperature and obesity. We aimed to assess the associations between body temperature and several adiposity and metabolic markers according to gender and menopausal status in a large population-based sample. Methods The data collected between 2009 and 2012 from 4224 participants (mean age 57.3 ± 10.4 years, 2225 women) of the CoLaus study (Lausanne, Switzerland). Body temperature was measured at the tympanic membrane. Results Mean body temperature was 36.1 ± 0.4, 36.4 ± 0.4 and 36.3 ± 0.4 °C in men, premenopausal, and postmenopausal women, respectively (p < 0.001). In men and postmenopausal women, body temperature was positively and significantly (p < 0.05) associated with body mass index (Spearman correlation coefficients 0.157 and 0.083, respectively), waist (r = 0.163 and r = 0.104), waist to hip ratio (r = 0.187 and r = 0.132), body area (r = 0.094 and r = 0.085), resting heart rate (r = 0.227 and r = 182), glucose (r = 0.104 and r = 0.088) and insulin (r = 0.148 and r = 0.117). Except for body area and BMI in postmenopausal women, all associations remained significant after multivariable adjustment. In premenopausal women, body temperature was positively associated with resting heart rate (r = 0.140) and insulin (r = 0.170), and no significant associations were found after multivariable adjustment. Conclusion Body temperature is strongly associated with obesity markers in men and postmenopausal women. The absence of association in premenopausal women might be due to the influence of the menstrual cycle.
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Affiliation(s)
- François Bastardot
- Department of Medicine, Internal Medicine, Lausanne University hospital, Lausanne, Switzerland
| | - Pedro Marques-Vidal
- Department of Medicine, Internal Medicine, Lausanne University hospital, Lausanne, Switzerland
| | - Peter Vollenweider
- Department of Medicine, Internal Medicine, Lausanne University hospital, Lausanne, Switzerland.
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21
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Grant AD, Wilsterman K, Smarr BL, Kriegsfeld LJ. Evidence for a Coupled Oscillator Model of Endocrine Ultradian Rhythms. J Biol Rhythms 2018; 33:475-496. [PMID: 30132387 DOI: 10.1177/0748730418791423] [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: 12/23/2022]
Abstract
Whereas long-period temporal structures in endocrine dynamics have been well studied, endocrine rhythms on the scale of hours are relatively unexplored. The study of these ultradian rhythms (URs) has remained nascent, in part, because a theoretical framework unifying ultradian patterns across systems has not been established. The present overview proposes a conceptual coupled oscillator network model of URs in which oscillating hormonal outputs, or nodes, are connected by edges representing the strength of node-node coupling. We propose that variable-strength coupling exists both within and across classic hormonal axes. Because coupled oscillators synchronize, such a model implies that changes across hormonal systems could be inferred by surveying accessible nodes in the network. This implication would at once simplify the study of URs and open new avenues of exploration into conditions affecting coupling. In support of this proposed framework, we review mammalian evidence for (1) URs of the gut-brain axis and the hypothalamo-pituitary-thyroid, -adrenal, and -gonadal axes, (2) UR coupling within and across these axes; and (3) the relation of these URs to body temperature. URs across these systems exhibit behavior broadly consistent with a coupled oscillator network, maintaining both consistent URs and coupling within and across axes. This model may aid the exploration of mammalian physiology at high temporal resolution and improve the understanding of endocrine system dynamics within individuals.
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Affiliation(s)
- Azure D Grant
- The Helen Wills Neuroscience Institute, University of California, Berkeley, California
| | - Kathryn Wilsterman
- Department of Integrative Biology, University of California, Berkeley, California
| | - Benjamin L Smarr
- Department of Psychology, University of California, Berkeley, California
| | - Lance J Kriegsfeld
- The Helen Wills Neuroscience Institute, University of California, Berkeley, California.,Department of Psychology, University of California, Berkeley, California
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22
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Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, Li ME, Yu R, Kleinridders A, Pothos EN, Kahn CR. Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest 2018; 128:2914-2926. [PMID: 29664737 DOI: 10.1172/jci99366] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/10/2018] [Indexed: 01/16/2023] Open
Abstract
Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states.
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Affiliation(s)
- Weikang Cai
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Chang Xue
- Program in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences and Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Masaji Sakaguchi
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Metabolic Medicine, Kumamoto University, Kumamoto, Japan
| | - Masahiro Konishi
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Alireza Shirazian
- Public Health and Professional Degree Programs, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Heather A Ferris
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Mengyao E Li
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Ruichao Yu
- Section of Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Andre Kleinridders
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.,National Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Emmanuel N Pothos
- Program in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences and Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
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Uchida Y, Onishi K, Tokizawa K, Nagashima K. Regional differences of cFos immunoreactive cells in the preoptic areas in hypothalamus associated with heat and cold responses in mice. Neurosci Lett 2018; 665:130-134. [PMID: 29183691 DOI: 10.1016/j.neulet.2017.11.053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 11/21/2017] [Accepted: 11/24/2017] [Indexed: 10/18/2022]
Abstract
cFos expression in the preoptic area (PO), which is thermoregulatory center increased by both heat and cold exposures; however, the regional difference is unknown yet. We aimed to determine if cFos expression in the PO was regionally different between heat and cold exposures. Mice were exposed to 27, 10, or 38°C for 90min, and body temperature (Tb) was measured. cFos-immunoreactive (cFos-IR) cells in the PO were counted by separating the PO into the ventral and dorsal parts in the rostral (bregma 0.38mm), central (-0.10mm), and caudal (-0.46mm) planes. Tb at 10°C remained unchanged; however, it increased at 38°C. Counts of cFos-IR cells in all areas were greater at 38°C than at 27°C. In the dorsal and ventral parts of the central and the dorsal part of caudal PO, counts of cFos-IR cells were greater at 10°C than at 27°C. In conclusion, the areas of increased cFos expression in the PO in the heat were different that in the cold in mice.
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Affiliation(s)
- Yuki Uchida
- Body Temperature and Fluid Laboratory, Faculty of Human Sciences, Waseda University, Saitama, Japan
| | - Keisuke Onishi
- Body Temperature and Fluid Laboratory, Faculty of Human Sciences, Waseda University, Saitama, Japan
| | - Ken Tokizawa
- Body Temperature and Fluid Laboratory, Faculty of Human Sciences, Waseda University, Saitama, Japan
| | - Kei Nagashima
- Body Temperature and Fluid Laboratory, Faculty of Human Sciences, Waseda University, Saitama, Japan; Institute of Applied Brain Sciences, Waseda University, Saitama, Japan.
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Abstract
Brown adipose tissue (BAT) is specialized to both store and expend chemical energy making it an ideal therapeutic target for various metabolic diseases. Fatty acids derived from lipid droplets within brown adipocytes acting on mitochondrial uncoupling protein 1 (UCP1) were long thought to be essential for non-shivering thermogenesis. Here, the roles of white adipose tissue and the liver in the provision of fuel to BAT as part of a coordinated response to temperature and dietary challenges are described. UCP1-independent modes of brown adipocyte heat production are also highlighted. A model that accommodates the findings obtained so far is further presented in which according to the conditions imposed on brown adipocytes, the relative contributions of circulating lipids and glucose for their normal function varies. Gaining deeper insight into the molecular processes which poise brown adipocytes to protect against whole-body thermal and energy imbalance represents a promising future area of metabolic research.
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Affiliation(s)
- Mohammed K. Hankir
- Department of Experimental Surgery, University Hospital Wuerzburg, Wuerzburg, Bavaria, Germany
- German Research Foundation Collaborative Research Center in Obesity Mechanisms, University of Leipzig, Leipzig, Saxony, Germany
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25
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Abstract
Homeotherms maintain their core body temperature within a narrow range by employing multiple redundant mechanisms to control heat production and dissipation. Preoptic area/anterior hypothalamic (PO/AH) neurons receive thermal signals from peripheral and deep-body thermoreceptors as well as hormonal and metabolic signals. A population of PO/AH neurons termed warm-sensitive increase their firing temperature with warming and are considered central thermoreceptors. Electrophysiologic and pharmacologic experiments have provided descriptions of their characteristics and signaling mechanisms. These studies have also allowed insights into the mechanisms by which neurochemicals important in thermoregulation exert their influence. Finally, the cellular mechanism involved in the interactions between thermoregulation and other aspects of homeostasis, such as energy metabolism and osmoregulation, have started to be unraveled.
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26
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Abstract
Classic lesion and physiology experiments identified the hypothalamic preoptic area as a pivotal region in the regulation of temperature homeostasis. The preoptic area can sense changes in local temperature, receives information about ambient temperature, contributes to fever, and can affect thermoregulation in response to several biologic signals. Electrophysiologic studies indicate that these actions are mediated by a neuronal circuitry that comprises temperature-sensitive as well as temperature-insensitive neurons. Little is known on the molecules that may be required for central thermosensation and much of the efforts towards their identification was done for warm-sensitive neurons. Here we summarize the current knowledge on the subject as well as what the search for these molecules revealed about warm-sensitive neurons.
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Affiliation(s)
- Bruno Conti
- Departments of Molecular Medicine and of Neuroscience, Dorris Neuroscience Center, Scripps Research Institute, La Jolla, CA, United States.
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27
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Arginine vasopressin antagonizes the effects of prostaglandin E 2 on the spontaneous activity of warm-sensitive and temperature-insensitive neurons in the medial preoptic area in rats. Neurosci Lett 2017; 662:59-64. [PMID: 28988972 DOI: 10.1016/j.neulet.2017.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 09/13/2017] [Accepted: 10/02/2017] [Indexed: 10/18/2022]
Abstract
Arginine vasopressin (AVP) plays an important role in thermoregulation and antipyresis. We have demonstrated that AVP could change the spontaneous activity of thermosensitive and temperature insensitive neurons in the preoptic area. However, whether AVP influences the effects of prostaglandin E2 (PGE2) on the spontaneous activity of neurons in the medial preoptic area (MPO) remains unclear. Our experiment showed that PGE2 decreased the spontaneous activity of warm-sensitive neurons, and increased that of low-slope temperature-insensitive neurons in the MPO. AVP attenuated the inhibitory effect of PGE2 on warm-sensitive neurons, and reversed the excitatory effect of PGE2 on low-slope temperature-insensitive neurons, demonstrating that AVP antagonized the effects of PGE2 on the spontaneous activity of these neurons. The effect of AVP was suppressed by an AVP V1a receptor antagonist, suggesting that V1a receptor mediated the action of AVP. We also demonstrated that AVP attenuated the PGE2-induced decrease in the prepotential's rate of rise in warm-sensitive neurons and the PGE2-induced increase in that in low-slope temperature-insensitive neurons through the V1a receptor. Together, these data indicated that AVP antagonized the PGE2-induced change in the spontaneous activity of warm-sensitive and low-slope temperature-insensitive neurons in the MPO partly by reducing the PGE2-induced change in the prepotential of these neurons in a V1a receptor-dependent manner.
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Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction. Proc Natl Acad Sci U S A 2017; 114:9731-9736. [PMID: 28827363 DOI: 10.1073/pnas.1617876114] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
When food resources are scarce, endothermic animals can lower core body temperature (Tb). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrus-specific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent Tb regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.
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The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis. J Neurosci 2017; 36:5170-80. [PMID: 27147667 DOI: 10.1523/jneurosci.3919-15.2016] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 04/04/2016] [Indexed: 11/21/2022] Open
Abstract
UNLABELLED The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons. SIGNIFICANCE STATEMENT Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.
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Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice. Sci Rep 2017; 7:3326. [PMID: 28607386 PMCID: PMC5468226 DOI: 10.1038/s41598-017-03406-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023] Open
Abstract
Modern life involves chronic circadian disruption through artificial light and these disruptions are associated with numerous mental and physical health maladies. Because the developing nervous system is particularly vulnerable to perturbation, we hypothesized that early-life circadian disruption would negatively impact offspring development and adult function. Pregnant mice were subjected to chronic circadian disruption from the time of uterine implantation through weaning. To dissociate in utero from postnatal effects, a subset of litters was cross-fostered at birth from disrupted dams to control dams and vice versa. Postnatal circadian disruption was associated with reduced adult body mass, social avoidance, and hyperactivity. In utero disruption resulted in more pronounced social avoidance and hyperactivity, phenotypes not abrogated by cross-fostering to control mothers. To examine whether circadian disruption affects development by acting as an early life stressor, we examined birthweight, litter size, maternal cannibalism, and epigenetic modifications. None of these variables differed between control and disrupted dams, or resembled patterns seen following early-life stress. Our findings indicate that developmental chronic circadian disruption permanently affects somatic and behavioral development in a stage-of-life-dependent manner, independent of early life stress mechanisms, underscoring the importance of temporal structure during development, both in utero and early postnatal life.
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Khan MZ, He L. Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein-coupled receptors. Psychopharmacology (Berl) 2017; 234:1181-1207. [PMID: 28289782 DOI: 10.1007/s00213-017-4586-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 02/27/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND In the central nervous system (CNS), G protein-coupled receptors (GPCRs) are the most fruitful targets for neuropsychopharmacological drug development. Rhodopsin (class A) is the most studied class of GPCR and includes orphan receptors for which the endogenous ligand is not known or is unclear. Characterization of orphan GPCRs has proven to be challenging, and the production pace of GPCR-based drugs has been incredibly slow. OBJECTIVE Determination of the functions of these receptors may provide unexpected insight into physiological and neuropathological processes. Advances in various methods and techniques to investigate orphan receptors including in situ hybridization and knockdown/knockout (KD/KO) showed extensive expression of these receptors in the mammalian brain and unmasked their physiological and neuropathological roles. Due to these rapid progress and development, orphan GPCRs are rising as a new and promising class of drug targets for neurodegenerative diseases and psychiatric disorders. CONCLUSION This review presents a neuropsychopharmacological perspective of 26 orphan receptors of rhodopsin (class A) family, namely GPR3, GPR6, GPR12, GPR17, GPR26, GPR35, GPR39, GPR48, GPR49, GPR50, GPR52, GPR55, GPR61, GPR62, GPR63, GPR68, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR153, GPR162, GPR171, and TAAR6. We discussed the expression of these receptors in mammalian brain and their physiological roles. Furthermore, we have briefly highlighted their roles in neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation, inflammatory pain, bipolar and schizophrenic disorders, epilepsy, anxiety, and depression.
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Affiliation(s)
- Muhammad Zahid Khan
- Department of Pharmacology, China Pharmaceutical University, No. 24 Tong Jia Xiang, Nanjing, Jiangsu Province, 210009, China.
| | - Ling He
- Department of Pharmacology, China Pharmaceutical University, No. 24 Tong Jia Xiang, Nanjing, Jiangsu Province, 210009, China
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Smarr BL, Grant AD, Zucker I, Prendergast BJ, Kriegsfeld LJ. Sex differences in variability across timescales in BALB/c mice. Biol Sex Differ 2017; 8:7. [PMID: 28203366 PMCID: PMC5301430 DOI: 10.1186/s13293-016-0125-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 12/26/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Females are markedly underinvestigated in the biological and behavioral sciences due to the presumption that cyclic hormonal changes across the ovulatory cycle introduce excess variability to measures of interest in comparison to males. However, recent analyses indicate that male and female mice and rats exhibit comparable variability across numerous physiological and behavioral measures, even when the stage of the estrous cycle is not considered. Hormonal changes across the ovulatory cycle likely contribute cyclic, intra-individual variability in females, but the source(s) of male variability has, to our knowledge, not been investigated. It is unclear whether male variability, like that of females, is temporally structured and, therefore, quantifiable and predictable. Finally, whether males and females exhibit variability on similar time scales has not been explored. METHODS These questions were addressed by collecting chronic, high temporal resolution locomotor activity (LA) and core body temperature (CBT) data from male and female BALB/c mice. RESULTS Contrary to expectation, males are more variable than females over the course of the day (diel variability) and exhibit higher intra-individual daily range than females in both LA and CBT. Between mice of a given sex, variability is comparable for LA but the inter-individual daily range in CBT is greater for males. To identify potential rhythmic processes contributing to these sex differences, we employed wavelet transformations across a range of periodicities (1-39 h). CONCLUSIONS Although variability in circadian power is comparable between the sexes for both LA and CBT, infradian variability is greater in females and ultradian variability is greater in males. Thus, exclusion of female mice from studies because of estrous cycle variability may increase variance in investigations where only male measures are collected over a span of several hours and limit generalization of findings from males to females.
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Affiliation(s)
- Benjamin L. Smarr
- Department of Psychology, University of California, Berkeley, CA 94720 USA
| | - Azure D. Grant
- Department of Psychology, University of California, Berkeley, CA 94720 USA
| | - Irving Zucker
- Department of Psychology, University of California, Berkeley, CA 94720 USA
- Department of Integrative Biology, University of California, Berkeley, CA USA
| | | | - Lance J. Kriegsfeld
- Department of Psychology, University of California, Berkeley, CA 94720 USA
- The Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720 USA
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Abstract
Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function.
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Affiliation(s)
- Liping Luo
- Department of Metabolism and EndocrinologyMetabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital,
Central South University, Changsha, Hunan, China
| | - Meilian Liu
- Department of Metabolism and EndocrinologyMetabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital,
Central South University, Changsha, Hunan, China
- Department of Biochemistry and Molecular BiologyUniversity of New Mexico Health Sciences Center,
Albuquerque, New Mexico, USA
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34
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Contribution of adaptive thermogenesis to the hypothalamic regulation of energy balance. Biochem J 2016; 473:4063-4082. [DOI: 10.1042/bcj20160012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 08/13/2016] [Accepted: 08/30/2016] [Indexed: 12/12/2022]
Abstract
Obesity and its related disorders are among the most pervasive diseases in contemporary societies, and there is an urgent need for new therapies and preventive approaches. Given (i) our poor social capacity to correct unhealthy habits, and (ii) our evolutionarily genetic predisposition to store excess energy as fat, the current environment of caloric surplus makes the treatment of obesity extremely difficult. During the last few decades, an increasing number of methodological approaches have increased our knowledge of the neuroanatomical basis of the control of energy balance. Compelling evidence underlines the role of the hypothalamus as a homeostatic integrator of metabolic information and its ability to adjust energy balance. A greater understanding of the neural basis of the hypothalamic regulation of energy balance might indeed pave the way for new therapeutic targets. In this regard, it has been shown that several important peripheral signals, such as leptin, thyroid hormones, oestrogens and bone morphogenetic protein 8B, converge on common energy sensors, such as AMP-activated protein kinase to modulate sympathetic tone on brown adipose tissue. This knowledge may open new ways to counteract the chronic imbalance underlying obesity. Here, we review the current state of the art on the role of hypothalamus in the regulation of energy balance with particular focus on thermogenesis.
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Gastrin-releasing peptide receptor mediates the excitation of preoptic GABAergic neurons by bombesin. Neurosci Lett 2016; 633:262-267. [PMID: 27693662 DOI: 10.1016/j.neulet.2016.09.045] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 09/19/2016] [Accepted: 09/25/2016] [Indexed: 12/31/2022]
Abstract
Bombesin, a pan agonist of the bombesin-like peptide receptor family, elicits potent hypothermia when applied centrally. The signaling mechanisms involved are not known. Here we report that GABAergic preoptic neurons express gastrin-releasing peptide (GRP) receptors and are directly excited by GRP or bombesin. This effect was abolished by a GRP receptor antagonist. A partially overlapping group of preoptic GABAergic neurons express bombesin-like receptor 3 (BRS3), however their activation results in a decrease in firing rate. The excitatory effects of bombesin or GRP were not affected by BRS3 antagonist. GRP activated a Ca2+-dependent inward nonselective cationic current and Ca2+ release from intracellular stores. Our data indicate that GRP receptors mediate the excitatory effects of bombesin in preoptic neurons.
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Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring HU. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Physiol Rev 2016; 96:1169-209. [PMID: 27489306 DOI: 10.1152/physrev.00032.2015] [Citation(s) in RCA: 383] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.
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Affiliation(s)
- Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Manfred Hallschmid
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany
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Tönük ŞB, Serin E, Ayhan FF, Yorgancioglu ZR. The effects of physical therapeutic agents on serum levels of stress hormones in patients with osteoarthritis. Medicine (Baltimore) 2016; 95:e4660. [PMID: 27583888 PMCID: PMC5008572 DOI: 10.1097/md.0000000000004660] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
To investigate the effects of physical agents on the levels of stress hormones in patients with osteoarthritis (OA).Transcutaneous electrical nerve stimulation, hot packs, and therapeutic ultrasound were applied to the lumbar region and knees of patients with OA. Blood samples were taken for the measurement of the serum levels of glucose, insulin (INS), growth hormone (GH), prolactin (PRL), cortisol (COR), and plasma adrenocorticotropic hormone (ACTH) immediately before and after the 1st session, to investigate the acute effects of those physical agents on the endocrine system. The hormone levels were also measured every 5 sessions in a total of 10 sessions. The treatment response was also evaluated by using the visual analogue scale (VAS), Roland Morris Disability Questionnaire (RMDQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) throughout the therapy period.After the 1st session, there was a decrease in INS levels and a mild decrease in PRL levels (P = 0.001 and P < 0.05, respectively). Throughout the 10-session therapy period, the INS levels increased, whereas the ACTH and COR levels decreased (P < 0.05 for all). The VAS-spine, RMDQ, VAS-knee, and WOMAC scores decreased (P = 0.001 for VAS-spine and P < 0.001 for all others). A positive correlation was detected between the changes in serum COR and WOMAC-pain score (P < 0.05).Although the combination therapy caused changes in INS level accompanied with steady glucose levels, the application of physical agents did not adversely affect the hormone levels. The decrease in ACTH and COR levels may be attributed to the analgesic effect of agents and may be an indicator of patient comfort through a central action.
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Affiliation(s)
- Şükrü Burak Tönük
- Department of Physical Medicine and Rehabilitation, School of Medicine, Abant Izzet Baysal University, Bolu
- Correspondence: Şükrü Burak Tönük, Abant Izzet Baysal Üniversitesi, Izzet Baysal Fizik Tedavi ve Rehabilitasyon Hastanesi, 14020 Karacasu Bolu, Turkey (e-mail: )
| | - Erdinc Serin
- Department of Medical Biochemistry, Istanbul Research and Education Hospital, Istanbul
| | - Fikriye Figen Ayhan
- Department of Physical Medicine and Rehabilitation, Ankara Research and Education Hospital, Ankara, Turkey
| | - Zeynep Rezan Yorgancioglu
- Department of Physical Medicine and Rehabilitation, Ankara Research and Education Hospital, Ankara, Turkey
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Smarr BL, Zucker I, Kriegsfeld LJ. Detection of Successful and Unsuccessful Pregnancies in Mice within Hours of Pairing through Frequency Analysis of High Temporal Resolution Core Body Temperature Data. PLoS One 2016; 11:e0160127. [PMID: 27467519 PMCID: PMC4965159 DOI: 10.1371/journal.pone.0160127] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 07/13/2016] [Indexed: 11/22/2022] Open
Abstract
Many controllable factors negatively impact fetal development, underscoring the importance of early pregnancy detection and identification of events that reliably predict potential complications. Clinically, core body temperature (CBT) is used to aid family planning and pregnancy detection. However, such temperature data typically are gathered in single, daily measurements. In animal studies, interventions or cell/tissue harvesting at defined stages of fetal development are arduous, requiring timed mating by trained observers. The value of continuous temperature measurements remains largely unexplored, but the advent of small, inexpensive, and increasingly ubiquitous, accurate sensor devices makes continuous measures feasible. Here, using a mouse model, we show that continuous, 1-min resolution CBT measurements reliably allow for the earliest and most accurate detection of pregnancy (100%, within 14 h of initial pairing), without requiring interaction with the animal for data collection. This method also reveals a subset of females that exhibit a pregnancy-like response following pairing that persists for a variable number of days. Application of wavelet analysis that permits frequency analysis while preserving temporal resolution, uncovers significant differences in ultradian frequencies of CBT; these rhythms are significantly increased in the 12 h after the day of pairing for pregnancies carried to term compared to apparent pregnancies that failed. High temporal resolution CBT and wavelet analysis permit strikingly early detection and separation of successful pregnancies and pregnancy-like events.
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Affiliation(s)
- Benjamin L. Smarr
- Department of Psychology, University of California, Berkeley, United States of America
| | - Irving Zucker
- Department of Psychology, University of California, Berkeley, United States of America
- Department of Integrative Biology, University of California, Berkeley, United States of America
| | - Lance J. Kriegsfeld
- Department of Psychology, University of California, Berkeley, United States of America
- The Helen Wills Neuroscience Institute, University of California, Berkeley, United States of America
- * E-mail:
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Abstract
The marked (18)F-flurodeoxyglucose uptake by brown adipose tissue (BAT) enabled its identification in human positron emission tomography imaging studies. In this Perspective, we discuss how glucose extraction by BAT and beige adipose tissue (BeAT) sufficiently impacts on glycemic control. We then present a unique overview of the central circuits modulated by gluco-regulatory hormones, temperature, and glucose itself, which converge on sympathetic preganglionic neurons and whose activation syphon circulating glucose into BAT/BeAT. Targeted stimulation of the sympathetic nervous system at specific nodes to selectively recruit BAT/BeAT may represent a safe and effective means of treating diabetes.
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Affiliation(s)
- Mohammed K Hankir
- Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, University of Leipzig, Leipzig, Saxony 04103, Germany.
| | - Michael A Cowley
- Department of Physiology, Monash Obesity and Diabetes Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Wiebke K Fenske
- Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, University of Leipzig, Leipzig, Saxony 04103, Germany
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Basso A, Del Bello G, Piacenza F, Giacconi R, Costarelli L, Malavolta M. Circadian rhythms of body temperature and locomotor activity in aging BALB/c mice: early and late life span predictors. Biogerontology 2016; 17:703-14. [PMID: 26820297 DOI: 10.1007/s10522-016-9635-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 01/20/2016] [Indexed: 01/16/2023]
Abstract
Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed.
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Affiliation(s)
- Andrea Basso
- Nutrition and Aging Centre, Scientific and Technological Pole - INRCA - National Institute of Health and Sciences on Ageing, Via Birarelli 8, 60121, Ancona, Italy
| | - Giovanna Del Bello
- Nutrition and Aging Centre, Scientific and Technological Pole - INRCA - National Institute of Health and Sciences on Ageing, Via Birarelli 8, 60121, Ancona, Italy
| | - Francesco Piacenza
- Nutrition and Aging Centre, Scientific and Technological Pole - INRCA - National Institute of Health and Sciences on Ageing, Via Birarelli 8, 60121, Ancona, Italy
| | - Robertina Giacconi
- Nutrition and Aging Centre, Scientific and Technological Pole - INRCA - National Institute of Health and Sciences on Ageing, Via Birarelli 8, 60121, Ancona, Italy
| | - Laura Costarelli
- Nutrition and Aging Centre, Scientific and Technological Pole - INRCA - National Institute of Health and Sciences on Ageing, Via Birarelli 8, 60121, Ancona, Italy
| | - Marco Malavolta
- Nutrition and Aging Centre, Scientific and Technological Pole - INRCA - National Institute of Health and Sciences on Ageing, Via Birarelli 8, 60121, Ancona, Italy.
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Anderson JP, Parikh JR, Shenfeld DK, Ivanov V, Marks C, Church BW, Laramie JM, Mardekian J, Piper BA, Willke RJ, Rublee DA. Reverse Engineering and Evaluation of Prediction Models for Progression to Type 2 Diabetes: An Application of Machine Learning Using Electronic Health Records. J Diabetes Sci Technol 2015; 10:6-18. [PMID: 26685993 PMCID: PMC4738229 DOI: 10.1177/1932296815620200] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Application of novel machine learning approaches to electronic health record (EHR) data could provide valuable insights into disease processes. We utilized this approach to build predictive models for progression to prediabetes and type 2 diabetes (T2D). METHODS Using a novel analytical platform (Reverse Engineering and Forward Simulation [REFS]), we built prediction model ensembles for progression to prediabetes or T2D from an aggregated EHR data sample. REFS relies on a Bayesian scoring algorithm to explore a wide model space, and outputs a distribution of risk estimates from an ensemble of prediction models. We retrospectively followed 24 331 adults for transitions to prediabetes or T2D, 2007-2012. Accuracy of prediction models was assessed using an area under the curve (AUC) statistic, and validated in an independent data set. RESULTS Our primary ensemble of models accurately predicted progression to T2D (AUC = 0.76), and was validated out of sample (AUC = 0.78). Models of progression to T2D consisted primarily of established risk factors (blood glucose, blood pressure, triglycerides, hypertension, lipid disorders, socioeconomic factors), whereas models of progression to prediabetes included novel factors (high-density lipoprotein, alanine aminotransferase, C-reactive protein, body temperature; AUC = 0.70). CONCLUSIONS We constructed accurate prediction models from EHR data using a hypothesis-free machine learning approach. Identification of established risk factors for T2D serves as proof of concept for this analytical approach, while novel factors selected by REFS represent emerging areas of T2D research. This methodology has potentially valuable downstream applications to personalized medicine and clinical research.
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Labbé SM, Caron A, Lanfray D, Monge-Rofarello B, Bartness TJ, Richard D. Hypothalamic control of brown adipose tissue thermogenesis. Front Syst Neurosci 2015; 9:150. [PMID: 26578907 PMCID: PMC4630288 DOI: 10.3389/fnsys.2015.00150] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 10/20/2015] [Indexed: 12/21/2022] Open
Abstract
It has long been known, in large part from animal studies, that the control of brown adipose tissue (BAT) thermogenesis is insured by the central nervous system (CNS), which integrates several stimuli in order to control BAT activation through the sympathetic nervous system (SNS). SNS-mediated BAT activity is governed by diverse neurons found in brain structures involved in homeostatic regulations and whose activity is modulated by various factors including oscillations of energy fluxes. The characterization of these neurons has always represented a challenging issue. The available literature suggests that the neuronal circuits controlling BAT thermogenesis are largely part of an autonomic circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In the present review, we recapitulate the latest progresses in regards to the hypothalamic regulation of BAT metabolism. We briefly addressed the role of the thermoregulatory pathway and its interactions with the energy balance systems in the control of thermogenesis. We also reviewed the involvement of the brain melanocortin and endocannabinoid systems as well as the emerging role of steroidogenic factor 1 (SF1) neurons in BAT thermogenesis. Finally, we examined the link existing between these systems and the homeostatic factors that modulate their activities.
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Affiliation(s)
- Sebastien M Labbé
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC, Canada
| | - Alexandre Caron
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC, Canada
| | - Damien Lanfray
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC, Canada
| | - Boris Monge-Rofarello
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC, Canada
| | - Timothy J Bartness
- Department of Biology, Center for Obesity Reversal (COR), Georgia State University Atlanta, GA, USA
| | - Denis Richard
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC, Canada
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Stouffer MA, Woods CA, Patel JC, Lee CR, Witkovsky P, Bao L, Machold RP, Jones KT, de Vaca SC, Reith MEA, Carr KD, Rice ME. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward. Nat Commun 2015; 6:8543. [PMID: 26503322 PMCID: PMC4624275 DOI: 10.1038/ncomms9543] [Citation(s) in RCA: 205] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 09/02/2015] [Indexed: 01/08/2023] Open
Abstract
Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices.
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Affiliation(s)
- Melissa A. Stouffer
- Department of Neuroscience and Physiology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
- Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Catherine A. Woods
- Center for Neural Science, New York University, 4 Washington Place, New York, New York 10003, USA
| | - Jyoti C. Patel
- Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Christian R. Lee
- Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Paul Witkovsky
- Department of Ophthalmology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Li Bao
- Department of Neuroscience and Physiology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
- Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Robert P. Machold
- Smilow Neuroscience Program, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Kymry T. Jones
- Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Soledad Cabeza de Vaca
- Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Maarten E. A. Reith
- Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Kenneth D. Carr
- Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
| | - Margaret E. Rice
- Department of Neuroscience and Physiology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
- Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
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Spaethling JM, Sanchez-Alavez M, Lee J, Xia FC, Dueck H, Wang W, Fisher SA, Sul JY, Seale P, Kim J, Bartfai T, Eberwine J. Single-cell transcriptomics and functional target validation of brown adipocytes show their complex roles in metabolic homeostasis. FASEB J 2015; 30:81-92. [PMID: 26304220 DOI: 10.1096/fj.15-273797] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 08/13/2015] [Indexed: 01/08/2023]
Abstract
Brown adipocytes (BAs) are specialized for adaptive thermogenesis and, upon sympathetic stimulation, activate mitochondrial uncoupling protein (UCP)-1 and oxidize fatty acids to generate heat. The capacity for brown adipose tissue (BAT) to protect against obesity and metabolic disease is recognized, yet information about which signals activate BA, besides β3-adrenergic receptor stimulation, is limited. Using single-cell transcriptomics, we confirmed the presence of mRNAs encoding traditional BAT markers (i.e., UCP1, expressed in 100% of BAs Adrb3, expressed in <50% of BAs) in mouse and have shown single-cell variability (>1000-fold) in their expression at both the mRNA and protein levels. We further identified mRNAs encoding novel markers, orphan GPCRs, and many receptors that bind the classic neurotransmitters, neuropeptides, chemokines, cytokines, and hormones. The transcriptome variability between BAs suggests a much larger range of responsiveness of BAT than previously recognized and that not all BAs function identically. We examined the in vivo functional expression of 12 selected receptors by microinjecting agonists into live mouse BAT and analyzing the metabolic response. In this manner, we expanded the number of known receptors on BAs at least 25-fold, while showing that the expression of classic BA markers is more complex and variable than previously thought.
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Affiliation(s)
- Jennifer M Spaethling
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Manuel Sanchez-Alavez
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - JaeHee Lee
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Feng C Xia
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Hannah Dueck
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Wenshan Wang
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Stephen A Fisher
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Jai-Yoon Sul
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Patrick Seale
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Junhyong Kim
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - Tamas Bartfai
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
| | - James Eberwine
- *Department of Pharmacology, Department of Genomics and Computational Biology, and Department of Cell and Developmental Biology, Perelman School of Medicine, and Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
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Abstract
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.
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46
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Abstract
Thermogenesis, the production of heat energy, in brown adipose tissue is a significant component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature in many species from mouse to man and plays a key role in elevating body temperature during the febrile response to infection. The sympathetic neural outflow determining brown adipose tissue (BAT) thermogenesis is regulated by neural networks in the CNS which increase BAT sympathetic nerve activity in response to cutaneous and deep body thermoreceptor signals. Many behavioral states, including wakefulness, immunologic responses, and stress, are characterized by elevations in core body temperature to which central command-driven BAT activation makes a significant contribution. Since energy consumption during BAT thermogenesis involves oxidation of lipid and glucose fuel molecules, the CNS network driving cold-defensive and behavioral state-related BAT activation is strongly influenced by signals reflecting the short- and long-term availability of the fuel molecules essential for BAT metabolism and, in turn, the regulation of BAT thermogenesis in response to metabolic signals can contribute to energy balance, regulation of body adipose stores and glucose utilization. This review summarizes our understanding of the functional organization and neurochemical influences within the CNS networks that modulate the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolic alterations in BAT thermogenesis and BAT energy expenditure that contribute to overall energy homeostasis and the autonomic support of behavior.
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Affiliation(s)
- Shaun F Morrison
- Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon
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47
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Spetter MS, Hallschmid M. Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease. Mol Pharm 2015; 12:2767-80. [PMID: 25880274 DOI: 10.1021/acs.molpharmaceut.5b00047] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Central nervous system control of metabolic function relies on the input of endocrine messengers from the periphery, including the pancreatic hormone insulin and the adipokine leptin. This concept primarily derives from experiments in animals where substances can be directly applied to the brain. A feasible approach to study the impact of peptidergic messengers on brain function in humans is the intranasal (IN) route of administration, which bypasses the blood-brain barrier and delivers neuropeptides to the brain compartment, but induces considerably less, if any, peripheral uptake than other administration modes. Experimental IN insulin administration has been extensively used to delineate the role of brain insulin signaling in the control of energy homeostasis, but also cognitive function in healthy humans. Clinical pilot studies have found beneficial effects of IN insulin in patients with memory deficits, suggesting that the IN delivery of this and other peptides bears some promise for new, selectively brain-targeted pharmaceutical approaches in the treatment of metabolic and cognitive disorders. More recently, experiments relying on the IN delivery of the hypothalamic hormone oxytocin, which is primarily known for its involvement in psychosocial processes, have provided evidence that oxytocin influences metabolic control in humans. The IN administration of leptin has been successfully tested in animal models but remains to be investigated in the human setting. We briefly summarize the literature on the IN administration of insulin, leptin, and oxytocin, with a particular focus on metabolic effects, and address limitations and perspectives of IN neuropeptide administration.
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Affiliation(s)
- Maartje S Spetter
- †Department of Medical Psychology and Behavioral Neurobiology, University of Tübingen, 72076 Tübingen, Germany
| | - Manfred Hallschmid
- †Department of Medical Psychology and Behavioral Neurobiology, University of Tübingen, 72076 Tübingen, Germany.,‡German Center for Diabetes Research (DZD), 72076 Tübingen, Germany.,§Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), 72076 Tübingen, Germany
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48
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Estimation of the core temperature control during ambient temperature changes and the influence of circadian rhythm and metabolic conditions in mice. J Therm Biol 2015; 51:47-54. [PMID: 25965017 DOI: 10.1016/j.jtherbio.2015.03.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 03/10/2015] [Accepted: 03/10/2015] [Indexed: 11/24/2022]
Abstract
It has been speculated that the control of core temperature is modulated by physiological demands. We could not prove the modulation because we did not have a good method to evaluate the control. In the present study, the control of core temperature in mice was assessed by exposing them to various ambient temperatures (Ta), and the influence of circadian rhythm and feeding condition was evaluated. Male ICR mice (n=20) were placed in a box where Ta was increased or decreased from 27°C to 40°C or to -4°C (0.15°C/min) at 0800 and 2000 (daytime and nighttime, respectively). Intra-abdominal temperature (Tcore) was monitored by telemetry. The relationship between Tcore and Ta was assessed. The range of Ta where Tcore was relatively stable (range of normothermia, RNT) and Tcore corresponding to the RNT median (regulated Tcore) were estimated by model analysis. In fed mice, the regression slope within the RNT was smaller in the nighttime than in the daytime (0.02 and 0.06, respectively), and the regulated Tcore was higher in the nighttime than in the daytime (37.5°C and 36.0°C, respectively). In the fasted mice, the slope remained unchanged, and the regulated Tcore decreased in the nighttime (0.05 and 35.9°C, respectively), while the slopes in the daytime became greater (0.13). Without the estimating individual thermoregulatory response such as metabolic heat production and skin vasodilation, the analysis of the Ta-Tcore relationship could describe the character of the core temperature control. The present results show that the character of the system changes depending on time of day and feeding conditions.
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49
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Abstract
Obesity is the result of disequilibrium between energy intake and energy expenditure (EE). Successful long-term weight loss is difficult to achieve with current strategies for the correction of this caloric imbalance. Non-shivering thermogenesis (NST) in brown adipose tissue (BAT) is a possible therapeutic target for the prevention and treatment of obesity and associated metabolic diseases. In recent years, more knowledge about the function and stimulation of bat has been obtained. The sympathetic nervous system (SNS) is currently seen as the main effector for brown fat function. Also, interplay between the thyroid axis and SNS plays an important role in BAT thermogenesis. Almost daily new pathways for the induction of BAT thermogenesis and 'browning' of white adipose tissue (WAT) are identified. Especially the activation of BAT via endogenous pathways has received strong scientific attention. Here we will discuss the relevance of several pathways in activating BAT and their implications for the treatment of obesity. In this review we will focus on the discussion of the most promising endocrine and paracrine pathways to stimulate BAT, by factors and pathways that naturally occur in the human body.
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Affiliation(s)
- Evie Broeders
- Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre , Maastricht , the Netherlands
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50
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Chong ACN, Greendyk RA, Zeltser LM. Distinct networks of leptin- and insulin-sensing neurons regulate thermogenic responses to nutritional and cold challenges. Diabetes 2015; 64:137-46. [PMID: 25125486 PMCID: PMC4274810 DOI: 10.2337/db14-0567] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Defense of core body temperature (Tc) can be energetically costly; thus, it is critical that thermoregulatory circuits are modulated by signals of energy availability. Hypothalamic leptin and insulin signals relay information about energy status and are reported to promote thermogenesis, raising the possibility that they interact to direct an appropriate response to nutritional and thermal challenges. To test this idea, we used an Nkx2.1-Cre driver to generate conditional knockouts (KOs) in mice of leptin receptor (L(2.1)KO), insulin receptor (I(2.1)KO), and double KOs of both receptors (D(2.1)KO). L(2.1)KOs are hyperphagic and obese, whereas I(2.1)KOs are similar to controls. D(2.1)KOs exhibit higher body weight and adiposity than L(2.1)KOs, solely due to reduced energy expenditure. At 20-22°C, fed L(2.1)KOs maintain a lower baseline Tc than controls, which is further decreased in D(2.1)KOs. After an overnight fast, some L(2.1)KOs dramatically suppress energy expenditure and enter a torpor-like state; this behavior is markedly enhanced in D(2.1)KOs. When fasted mice are exposed to 4°C, L(2.1)KOs and D(2.1)KOs both mount a robust thermogenic response and rapidly increase Tc. These observations support the idea that neuronal populations that integrate information about energy stores to regulate the defense of Tc set points are distinct from those required to respond to a cold challenge.
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Affiliation(s)
- Angie C N Chong
- Institute of Human Nutrition, Columbia University, New York, NY Naomi Berrie Diabetes Center, Columbia University, New York, NY
| | | | - Lori M Zeltser
- Naomi Berrie Diabetes Center, Columbia University, New York, NY Department of Pathology and Cell Biology, Columbia University, New York, NY
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