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1
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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2
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Zhao Y, Peng X, Wang Q, Zhang Z, Wang L, Xu Y, Yang H, Bai J, Geng D. Crosstalk Between the Neuroendocrine System and Bone Homeostasis. Endocr Rev 2024; 45:95-124. [PMID: 37459436 DOI: 10.1210/endrev/bnad025] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Indexed: 01/05/2024]
Abstract
The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.
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Affiliation(s)
- Yuhu Zhao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Xiaole Peng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Qing Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Zhiyu Zhang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Liangliang Wang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
- Department of Orthopedics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230022, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
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Abend Bardagi A, Dos Santos Paschoal C, Favero GG, Riccetto L, Alexandrino Dias ML, Guerra Junior G, Degasperi G. Leptin's Immune Action: A Review Beyond Satiety. Immunol Invest 2023; 52:117-133. [PMID: 36278927 DOI: 10.1080/08820139.2022.2129381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The adipose tissue is an endocrine organ that secretes adipokines such as leptin, which is one of the most important hormones for controlling satiety, metabolism, and energy homeostasis. This hormone acts in the regulation of innate and adaptive immune responses since immune cells have leptin receptors from which this hormone initiates its biological action. These receptors have been identified in hematopoietic stem cells in the bone marrow and mature immune cells, inducing signaling pathways mediated by JAK/STAT, PI3K, and ERK 1/2. It is known that the bone marrow also contains leptin-producing adipocytes, which are crucial for regulating hematopoiesis through largely unknown mechanisms. Therefore, we have reviewed the roles of leptin inside and outside the bone marrow, going beyond its action in the control of satiety.
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Affiliation(s)
- Alice Abend Bardagi
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Clarissa Dos Santos Paschoal
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Giovanna Ganem Favero
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Luisa Riccetto
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Maria Luisa Alexandrino Dias
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Gil Guerra Junior
- Center for Investigation in Pediatrics (CIPED), School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, Brazil
| | - Giovanna Degasperi
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
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4
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Boregowda SV, Nanjappa MK, Booker CN, Strivelli J, Supper VM, Cooke PS, Phinney DG. Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss. BIOLOGY 2022; 11:biology11091257. [PMID: 36138736 PMCID: PMC9495776 DOI: 10.3390/biology11091257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022]
Abstract
Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown. To determine if IP6K1 inhibition in obese mice affords protection against obesity-induced metabolic derangements and bone loss, we maintained 2-month-old mice on a normal chow control diet or HFD under thermal neutral conditions for 100 d. Beginning on day 40, HFD-fed mice were divided into two groups and administered daily injections of vehicle or the pan-IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine]. HFD-fed mice developed obesity, hyperglycemia, hyperlipidemia, and secondary osteoporosis, while TNP administration protected mice against HFD-induced metabolic and lipid derangements and preserved bone mass, mineral density, and trabecular microarchitecture, which correlated with reduced serum leptin levels, reduced marrow adiposity, and preservation of marrow resident skeletal stem/progenitor cells (SSPCs). TNP also exhibited hypotensive activity, an unrealized benefit of the drug, and its prolonged administration had no adverse impacts on spermatogenesis. Together, these data indicate that the inhibition of IP6K1 using selective inhibitors, such as TNP, may provide an effective strategy to manage obesity and T2DM due to its bone sparing effects.
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Affiliation(s)
- Siddaraju V. Boregowda
- Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
| | | | - Cori N. Booker
- Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
| | - Jacqueline Strivelli
- Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
| | - Valentina M. Supper
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32610, USA
| | - Paul S. Cooke
- Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, USA
| | - Donald G. Phinney
- Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
- Correspondence:
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Londraville RL, Tuttle M, Liu Q, Andronowski JM. Endospanin Is a Candidate for Regulating Leptin Sensitivity. Front Physiol 2022; 12:786299. [PMID: 35069248 PMCID: PMC8777038 DOI: 10.3389/fphys.2021.786299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/25/2021] [Indexed: 11/13/2022] Open
Abstract
The hypothesis advanced is that endospanin, a highly conserved vesicle traffic protein in vertebrates, regulates leptin sensitivity in bone signaling. The effects of leptin on bones are well-studied but without consensus on whether the increases in leptin signaling stimulate bone gain or loss. The bone response may depend on leptin sensitivity, and endospanin is an established modulator of leptin sensitivity. An argument is advanced to develop zebrafish models for specific leptin signaling pathways. Zebrafish have well-developed molecular tools (e.g., CRISPR) and the advantage of non-destructive sampling of bones in the form of scales. Using these tools, experiments are described to substantiate the role of endospanin in zebrafish bone dynamics.
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Affiliation(s)
- Richard L. Londraville
- Program in Integrated Bioscience, Department of Biology, University of Akron, Akron, OH, United States
| | - Matthew Tuttle
- Program in Integrated Bioscience, Department of Biology, University of Akron, Akron, OH, United States
| | - Qin Liu
- Program in Integrated Bioscience, Department of Biology, University of Akron, Akron, OH, United States
| | - Janna M. Andronowski
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. Johns, NL, Canada
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Mirhosseini Dehabadi S, Sayadi Shahraki M, Mahmoudieh M, Kalidari B, Melali H, Mousavi M, Ghourban Abadi M, Mirhosseini S. Bone health after bariatric surgery: Consequences, prevention, and treatment. Adv Biomed Res 2022; 11:92. [DOI: 10.4103/abr.abr_182_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/15/2021] [Accepted: 07/20/2021] [Indexed: 11/05/2022] Open
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Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts. NPJ Microgravity 2021; 7:49. [PMID: 34836964 PMCID: PMC8626488 DOI: 10.1038/s41526-021-00178-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 10/27/2021] [Indexed: 12/12/2022] Open
Abstract
Disuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on skeletal stem/progenitor cells (SSCs) is indeterminate. We modeled DO in mice by 8 and 14 weeks of hindlimb unloading (HU) or 8 weeks of unloading followed by 8 weeks of recovery (HUR) and monitored impacts on animal physiology and behavior, metabolism, marrow adipose tissue (MAT) volume, bone density and micro-architecture, and bone marrow (BM) leptin and tyrosine hydroxylase (TH) protein expression, and correlated multi-systems impacts of HU and HUR with the transcript profiles of Lin-LEPR+ SSCs and mesenchymal stem cells (MSCs) purified from BM. Using this integrative approach, we demonstrate that prolonged HU induces muscle atrophy, progressive bone loss, and MAT accumulation that paralleled increases in BM but not systemic leptin levels, which remained low in lipodystrophic HU mice. HU also induced SSC quiescence and downregulated bone anabolic and neurogenic pathways, which paralleled increases in BM TH expression, but had minimal impacts on MSCs, indicating a lack of HU memory in culture-expanded populations. Although most impacts of HU were reversed by HUR, trabecular micro-architecture remained compromised and time-resolved changes in the SSC transcriptome identified various signaling pathways implicated in bone formation that were unresponsive to HUR. These findings indicate that HU-induced alterations to the SSC transcriptome that persist after reloading may contribute to poor bone recovery.
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8
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Luo B, Zhou X, Tang Q, Yin Y, Feng G, Li S, Chen L. Circadian rhythms affect bone reconstruction by regulating bone energy metabolism. J Transl Med 2021; 19:410. [PMID: 34579752 PMCID: PMC8477514 DOI: 10.1186/s12967-021-03068-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/02/2021] [Indexed: 01/02/2023] Open
Abstract
Metabolism is one of the most complex cellular biochemical reactions, providing energy and substances for basic activities such as cell growth and proliferation. Early studies have shown that glucose is an important nutrient in osteoblasts. In addition, amino acid metabolism and fat metabolism also play important roles in bone reconstruction. Mammalian circadian clocks regulate the circadian cycles of various physiological functions. In vertebrates, circadian rhythms are mediated by a set of central clock genes: muscle and brain ARNT like-1 (Bmal1), muscle and brain ARNT like-2 (Bmal2), circadian rhythmic motion output cycle stagnates (Clock), cryptochrome 1 (Cry1), cryptochrome2 (Cry2), period 1 (Per1), period 2 (Per2), period 3 (Per3) and neuronal PAS domain protein 2 (Npas2). Negative feedback loops, controlled at both the transcriptional and posttranslational levels, adjust these clock genes in a diurnal manner. According to the results of studies on circadian transcriptomic studies in several tissues, most rhythmic genes are expressed in a tissue-specific manner and are affected by tissue-specific circadian rhythms. The circadian rhythm regulates several activities, including energy metabolism, feeding time, sleeping, and endocrine and immune functions. It has been reported that the circadian rhythms of mammals are closely related to bone metabolism. In this review, we discuss the regulation of the circadian rhythm/circadian clock gene in osteoblasts/osteoclasts and the energy metabolism of bone, and the relationship between circadian rhythm, bone remodeling, and energy metabolism. We also discuss the therapeutic potential of regulating circadian rhythms or changing energy metabolism on bone development/bone regeneration.
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Affiliation(s)
- Beibei Luo
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Xin Zhou
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ying Yin
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Guangxia Feng
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Shue Li
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
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Al-Aqbi M, Hart R, Ajuogu P, de Touw TV, McFarlane J, Smart N. Follicular fluid leptin as a marker for pregnancy outcomes in women undergoing IVF treatment: a systematic review and meta-analysis. HUM FERTIL 2020; 25:33-42. [PMID: 31910048 DOI: 10.1080/14647273.2019.1710271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Leptin is a hormone secreted mainly by the adipocytes with an essential role in the regulation of body weight. It acts on the reproductive axis at different sites, with stimulatory effects at the hypothalamus and pituitary and inhibitory interactions at the gonads. To investigate the influence of leptin on pregnancy outcomes in women undergoing IVF, we undertook a systematic review. A search of PubMed from 1966 to 2018 identified ten studies meeting the inclusion criteria. Outcomes were BMI, serum leptin level at hCG injection, serum and follicular fluid leptin level at the oocyte pick up, and serum 17β-oestradiol level at oocyte pick up time, oocytes retrieved and embryo transfer number. Results indicated that follicular fluid leptin concentrations at the oocyte pick up were significantly lower in women who became pregnant compared to those who did not (MD = -4.53 (ng/ml); 95% CI: -7.78, -1.78; p value < 0.006). In conclusion, elevated leptin concentrations in follicular fluid at oocyte pick up time is significantly associated with an adverse pregnancy outcome in women undergoing an IVF programme.
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Affiliation(s)
- Mohammed Al-Aqbi
- College of Agriculture, Wasit University, Wasit, Iraq.,School of Science and Technology, University of New England, Armidale, Australia
| | - Robert Hart
- School of Science and Technology, University of New England, Armidale, Australia
| | - Peter Ajuogu
- School of Science and Technology, University of New England, Armidale, Australia
| | - Tom Van de Touw
- School of Science and Technology, University of New England, Armidale, Australia
| | - James McFarlane
- School of Science and Technology, University of New England, Armidale, Australia
| | - Neil Smart
- School of Science and Technology, University of New England, Armidale, Australia
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10
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Abstract
PURPOSE OF REVIEW Osteocytes are the most abundant bone cells. They are completely encased in mineralized tissue, sitting inside lacunae that are connected by a multitude of canaliculi. In recent years, the osteocyte network has been shown to fulfill endocrine functions and to communicate with a number of other organs. This review addresses emerging knowledge on the connectome of the lacunocanalicular network in different types of bone tissue. RECENT FINDINGS Recent advances in three-dimensional imaging technology started to reveal parameters that are well known from general theory to characterize the function of networks, such as network density, degree of nodes, or shortest path length through the network. The connectome of the lacunocanalicular network differs in some aspects between lamellar and woven bone and seems to change with age. More research is needed to relate network structure to function, such as intercellular transport or communication and its role in mechanosensation, as well as to understand the effect of diseases.
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Affiliation(s)
- Richard Weinkamer
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14424, Potsdam, Germany
| | - Philip Kollmannsberger
- Center for Computational and Theoretical Biology, Universität Würzburg, Campus Hubland Nord 32, 97074, Würzburg, Germany
| | - Peter Fratzl
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14424, Potsdam, Germany.
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11
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Papageorgiou M, Kerschan-Schindl K, Sathyapalan T, Pietschmann P. Is Weight Loss Harmful for Skeletal Health in Obese Older Adults? Gerontology 2019; 66:2-14. [DOI: 10.1159/000500779] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 05/06/2019] [Indexed: 11/19/2022] Open
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12
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Hawkes CP, Mostoufi-Moab S. Fat-bone interaction within the bone marrow milieu: Impact on hematopoiesis and systemic energy metabolism. Bone 2019; 119:57-64. [PMID: 29550266 PMCID: PMC6139083 DOI: 10.1016/j.bone.2018.03.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/13/2018] [Indexed: 12/23/2022]
Abstract
The relationship between fat, bone and systemic metabolism is a growing area of scientific interest. Marrow adipose tissue is a well-recognized component of the bone marrow milieu and is metabolically distinct from current established subtypes of adipose tissue. Despite recent advances, the functional significance of marrow adipose tissue is still not clearly delineated. Bone and fat cells share a common mesenchymal stem cell (MSC) within the bone marrow, and hormones and transcription factors such as growth hormone, leptin, and peroxisomal proliferator-activated receptor γ influence MSC differentiation into osteoblasts or adipocytes. MSC osteogenic potential is more vulnerable than adipogenic potential to radiation and chemotherapy, and this confers a risk for an abnormal fat-bone axis in survivors following cancer therapy and bone marrow transplantation. This review provides a summary of data from animal and human studies describing the relationship between marrow adipose tissue and hematopoiesis, bone mineral density, bone strength, and metabolic function. The significance of marrow adiposity in other metabolic disorders such as osteoporosis, diabetes mellitus, and estrogen and growth hormone deficiency are also discussed. We conclude that marrow adipose tissue is an active endocrine organ with important metabolic functions contributing to bone energy maintenance, osteogenesis, bone remodeling, and hematopoiesis. Future studies on the metabolic role of marrow adipose tissue may provide the critical insight necessary for selecting targeted therapeutic interventions to improve altered hematopoiesis and augment skeletal remodeling in cancer survivors.
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Affiliation(s)
- C P Hawkes
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA
| | - S Mostoufi-Moab
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA; Perelman School of Medicine, Department of Pediatrics, University of Pennsylvania, Philadelphia, USA.
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13
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Abstract
It is from the discovery of leptin and the central nervous system as a regulator of bone remodeling that the presence of autonomic nerves within the skeleton transitioned from a mere histological observation to the mechanism whereby neurons of the central nervous system communicate with cells of the bone microenvironment and regulate bone homeostasis. This shift in paradigm sparked new preclinical and clinical investigations aimed at defining the contribution of sympathetic, parasympathetic, and sensory nerves to the process of bone development, bone mass accrual, bone remodeling, and cancer metastasis. The aim of this article is to review the data that led to the current understanding of the interactions between the autonomic and skeletal systems and to present a critical appraisal of the literature, bringing forth a schema that can put into physiological and clinical context the main genetic and pharmacological observations pointing to the existence of an autonomic control of skeletal homeostasis. The different types of nerves found in the skeleton, their functional interactions with bone cells, their impact on bone development, bone mass accrual and remodeling, and the possible clinical or pathophysiological relevance of these findings are discussed.
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Affiliation(s)
- Florent Elefteriou
- Department of Molecular and Human Genetics and Orthopedic Surgery, Center for Skeletal Medicine and Biology, Baylor College of Medicine , Houston, Texas
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14
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Metzger CE, Swift SN, Baek K, De Souza MJ, Bloomfield SA. Fat and Lean Mass Predict Bone Mass During Energy Restriction in Sedentary and Exercising Rodents. Front Physiol 2018; 9:1346. [PMID: 30356821 PMCID: PMC6190840 DOI: 10.3389/fphys.2018.01346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 09/06/2018] [Indexed: 01/25/2023] Open
Abstract
Energy restriction (ER) causes bone loss, but the impact of exercise during ER is less understood. In this study, we examined the impact of metabolic hormones and body composition on both total body bone mineral content (BMC) and local (proximal tibia) volumetric bone mineral density (vBMD) during short- (4 weeks) and long-term (12 weeks) ER with and without exercise in adult female rats. Our first goal was to balance energy between sedentary and exercising groups to determine the impact of exercise during ER. Second, we aimed to determine the strongest predictors of bone outcomes during ER with energy-matched exercising groups. Methods: Female Sprague–Dawley rats were divided into three sedentary groups (ad libitum, –20% ER, and –40% ER) and three exercising groups (ad libitum, –10% ER, and –30% ER). Approximately a 10% increase in energy expenditure was achieved via moderate treadmill running (∼60–100 min 4 days/week) in EX groups. n per group = 25–35. Data were analyzed as a 2 × 3 ANOVA with multiple linear regression to predict bone mass outcomes. Results: At 4 weeks, fat and lean mass and serum insulin-like growth factor-I (IGF-I) predicted total body BMC (R2 = 0.538). Fat mass decreased with ER at all levels, while lean mass was not altered. Serum IGF-I declined in the most severe ER groups (–40 and –30%). At 12 weeks, only fat and lean mass predicted total body BMC (R2 = 0.718). Fat mass declined with ER level regardless of exercise status and lean mass increased due to exercise (+5.6–6.7% vs. energy-matched sedentary groups). At the same time point, BMC declined with ER, but increased with exercise (+7.0–12.5% vs. energy-matched sedentary groups). None of our models predicted vBMD at the proximal tibia at either time point. Conclusion: Both fat and lean mass statistically predicted total body BMC during both short- and long-term ER. Fat and lean mass decreased with ER, while lean mass increased with EX at each energy level. Measures that predicted total body skeletal changes did not predict site-specific changes. These data highlight the importance of maintaining lean mass through exercise during periods of ER.
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Affiliation(s)
- Corinne E Metzger
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States
| | - Sibyl N Swift
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States
| | - Kyunghwa Baek
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States
| | - Mary Jane De Souza
- Department of Kinesiology, Pennsylvania State University, State College, PA, United States.,Department of Physiology, Pennsylvania State University, State College, PA, United States
| | - Susan A Bloomfield
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States
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15
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McCabe IC, Fedorko A, Myers MG, Leinninger G, Scheller E, McCabe LR. Novel leptin receptor signaling mutants identify location and sex-dependent modulation of bone density, adiposity, and growth. J Cell Biochem 2018; 120:4398-4408. [PMID: 30269370 DOI: 10.1002/jcb.27726] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 08/29/2018] [Indexed: 12/27/2022]
Abstract
Leptin, a hormone primarily produced by adipocytes, contributes to the regulation of bone health by modulating bone density, growth and adiposity. Upon leptin binding, multiple sites of the long form of the leptin receptor (LepRb) are phosphorylated to trigger activation of downstream signaling pathways. To address the role of LepRb-signaling pathways in bone health, we compared the effects of three LepRb mutations on bone density, adiposity, and growth in male and female mice. The ∆65 mutation, which lacks the known tyrosine phosphorylation sites, caused obesity and the most dramatic bone phenotype marked by excessive bone adiposity, osteoporosis, and decreased growth, consistent with the phenotype of db/db and ob/ob mice that fully lack leptin receptor signaling. Mutation of LepRb Tyr 1138 , which results in an inability to recruit and phosphorylate signal transducer and activator of transcription 3, also caused obesity, but bone loss and adiposity were more dominant in male mice and no growth defect was observed. In contrast, mutation of LepRb Tyr 985 , which blocks SHP2/SOCS3 recruitment to LepRb and contributes to leptin hypersensitivity, promoted increased femur bone density only in male mice, while marrow adiposity and bone growth were not affected. Additional analyses of vertebral trabecular bone volume indicate that only the Tyr 1138 mutant mice exhibit bone loss in vertebrae. Together, our findings suggest that the phosphorylation status of specific sites of the LepRb contribute to the sex- and location-dependent bone responses to leptin. Unraveling the mechanisms by which leptin responses are sex- and location-dependent can contribute to the development of uniquely targeted osteoporosis therapies.
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Affiliation(s)
- Ian C McCabe
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Alyssa Fedorko
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Martin G Myers
- Department of Molecular and Integrative Physiology, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan.,Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Gina Leinninger
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Erica Scheller
- Department of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, Missouri
| | - Laura R McCabe
- Department of Physiology, Michigan State University, East Lansing, Michigan.,Department of Radiology, Michigan State University, East Lansing, Michigan.,Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan
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16
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De Blasio MJ, Lanham SA, Blache D, Oreffo ROC, Fowden AL, Forhead AJ. Sex- and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus. Am J Physiol Regul Integr Comp Physiol 2018; 314:R781-R790. [PMID: 29443548 DOI: 10.1152/ajpregu.00351.2017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Widespread expression of leptin and its receptor in developing cartilage and bone suggests that leptin may regulate bone growth and development in the fetus. Using microcomputed tomography, this study investigated the effects of exogenous leptin and leptin receptor antagonism on aspects of bone structure in the sheep fetus during late gestation. From 125 to 130 days of gestation (term ~145 days), chronically catheterized singleton sheep fetuses were infused intravenously for 5 days with either saline (0.9% saline, n = 13), recombinant ovine leptin at two doses (0.6 mg·kg-1·day-1 LEP1, n = 10 or 1.4 mg·kg-1·day-1 LEP2, n = 7), or recombinant superactive ovine leptin receptor antagonist (4.6 mg·kg-1·day-1 SOLA, n = 6). No significant differences in plasma insulin-like growth factor-I, osteocalcin, calcium, inorganic phosphate, or alkaline phosphatase were observed between treatment groups. Total femur midshaft diameter and metatarsal lumen diameter were narrower in male fetuses treated with exogenous leptin. In a fixed length of femur midshaft, total and bone volumes were reduced by the higher dose of leptin; nonbone space volume was lower in both groups of leptin-treated fetuses. Leptin infusion caused increments in femur porosity and connectivity density, and vertebral trabecular thickness. Leptin receptor antagonism decreased trabecular spacing and increased trabecular number, degree of anisotrophy, and connectivity density in the lumbar vertebrae. The increase in vertebral porosity observed following leptin receptor antagonism was greater in the malecompared with female, fetuses. Therefore, leptin may have a role in the growth and development of the fetal skeleton, dependent on the concentration of leptin, sex of the fetus, and bone type examined.
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Affiliation(s)
- Miles J De Blasio
- Department of Physiology, Development, and Neuroscience, University of Cambridge , Cambridge , United Kingdom
| | - Stuart A Lanham
- Bone and Joint Research Group, Centre for Human Development, Stem Cells, and Regeneration, Institute of Developmental Sciences, University of Southampton , Southampton , United Kingdom
| | - Dominique Blache
- School of Animal Biology, University of Western Australia , Crawley , Australia
| | - Richard O C Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells, and Regeneration, Institute of Developmental Sciences, University of Southampton , Southampton , United Kingdom
| | - Abigail L Fowden
- Department of Physiology, Development, and Neuroscience, University of Cambridge , Cambridge , United Kingdom
| | - Alison J Forhead
- Department of Physiology, Development, and Neuroscience, University of Cambridge , Cambridge , United Kingdom.,Department of Biological and Medical Sciences, Oxford Brookes University , Oxford , United Kingdom
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17
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Philbrick KA, Martin SA, Colagiovanni AR, Branscum AJ, Turner RT, Iwaniec UT. Effects of hypothalamic leptin gene therapy on osteopetrosis in leptin-deficient mice. J Endocrinol 2018; 236:57-68. [PMID: 29191939 PMCID: PMC5771473 DOI: 10.1530/joe-17-0524] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 11/20/2017] [Indexed: 12/26/2022]
Abstract
Impaired resorption of cartilage matrix deposited during endochondral ossification is a defining feature of juvenile osteopetrosis. Growing, leptin-deficient ob/ob mice exhibit a mild form of osteopetrosis. However, the extent to which the disease is (1) self-limiting and (2) reversible by leptin treatment is unknown. We addressed the first question by performing histomorphometric analysis of femurs in rapidly growing (2-month-old), slowly growing (4-month-old) and skeletally mature (6-month-old) wild-type (WT) and ob/ob male mice. Absent by 6 months of age in WT mice, cartilage matrix persisted to varying extents in distal femur epiphysis, metaphysis and diaphysis in ob/ob mice, suggesting that the osteopetrotic phenotype is not entirely self-limiting. To address the second question, we employed hypothalamic recombinant adeno-associated virus (rAAV) gene therapy to restore leptin signaling in ob/ob mice. Two-month-old mice were randomized to one of the three groups: (1) untreated control, (2) rAAV-Leptin or (3) control vector rAAV-green fluorescent protein and vectors injected intracerebroventricularly. Seven months later, rAAV-leptin-treated mice exhibited no cartilage in the metaphysis and greatly reduced cartilage in the epiphysis and diaphysis. At the cellular level, the reduction in cartilage was associated with increased bone turnover. These findings (1) support the concept that leptin is important for normal replacement of cartilage by bone, and (2) demonstrate that osteopetrosis in ob/ob mice is bone-compartment-specific and reversible by leptin at skeletal sites capable of undergoing robust bone turnover.
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Affiliation(s)
- Kenneth A Philbrick
- Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
| | - Stephen A Martin
- Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
| | - Amy R Colagiovanni
- Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
| | - Adam J Branscum
- Biostatistics ProgramSchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
| | - Russell T Turner
- Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
- Center for Healthy Aging ResearchOregon State University, Corvallis, Oregon, USA
| | - Urszula T Iwaniec
- Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
- Center for Healthy Aging ResearchOregon State University, Corvallis, Oregon, USA
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18
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Lima JG, Nobrega LHC, Lima NN, Dos Santos MCF, Baracho MDFP, Bandeira F, Capistrano L, Freire Neto FP, Jeronimo SMB. Bone Density in Patients With Berardinelli-Seip Congenital Lipodystrophy Is Higher in Trabecular Sites and in Type 2 Patients. J Clin Densitom 2018; 21:61-67. [PMID: 27894728 DOI: 10.1016/j.jocd.2016.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 08/15/2016] [Accepted: 10/31/2016] [Indexed: 10/20/2022]
Abstract
Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty storing lipid in adipocytes, low body fat, hypoleptinemia, and hyperinsulinemia. We report here laboratory, bone mineral density (BMD), and bone mineral content findings of 21 patients (24.1 ± 8.4 yr old, 14 females, 18 diabetics, 5.3% total body fat) with BSCL. The mean leptin was very low (0.91 ± 0.42 ng/mL), and the mean values of the Z-scores for all studied sites were positive, except for the 33% radius (Z-score -0.5 standard deviation [SD]). Twelve patients (57.1%) had a BMD Z-score higher than +2.5 SD in at least 1 site. There was no significant difference in the Z-scores between males and females. None of type 1 (AGPAT2) patients had Z-scores higher than +2.5 SD, and these patients had a smaller Z-score of BMD total body (0.26 SD vs 1.90 SD, p = 0.022) and of bone mineral content (1.59 SD vs 3.3 SD, p = 0.032) than type 2 (seipin) patients. Insulin, as well as HOMAIR (homeostasis model assessment), correlated positively with the BMD of all sites, except for the 33% radius. Z-Scores on this site (33% radius) were the smallest of all. More than half of our patients with BSCL have BMD Z-scores higher than +2.5 SD on at least 1 site, and this increase is more pronounced in the trabecular sites and in type 2 patients.
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Affiliation(s)
- Josivan G Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL), Natal, RN, Brazil; Health Graduate Program, Centro de Ciencias da Saúde, UFRN, Natal, RN, Brazil.
| | - Lucia Helena C Nobrega
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL), Natal, RN, Brazil
| | - Natalia N Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL), Natal, RN, Brazil
| | - Marcel C F Dos Santos
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL), Natal, RN, Brazil
| | | | - Francisco Bandeira
- Division of Endocrinology and Diabetes, University of Pernambuco Medical School, Recife, Brazil
| | | | | | - Selma Maria B Jeronimo
- Instituto de Medicina Tropical do Rio Grande do Norte, Natal, RN, Brazil; Departamento de Bioquímica, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil; Institute of Science and Technology of Tropical Diseases (INCT-DT), Natal, RN, Brazil
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19
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The emerging role of bone marrow adipose tissue in bone health and dysfunction. J Mol Med (Berl) 2017; 95:1291-1301. [PMID: 29101431 DOI: 10.1007/s00109-017-1604-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/17/2017] [Accepted: 10/20/2017] [Indexed: 01/27/2023]
Abstract
Replacement of red hematopoietic bone marrow with yellow adipocyte-rich marrow is a conserved physiological process among mammals. The extent of this conversion is influenced by a wide array of pathological and non-pathological conditions. Of particular interest is the observation that some marrow adipocyte-inducing factors seem to oppose each other, for instance obesity and caloric restriction. Intriguingly, several important molecular characteristics of bone marrow adipose tissue (BMAT) are distinct from the classical depots of white and brown fat tissue. This depot of fat has recently emerged as an active part of the bone marrow niche that exerts paracrine and endocrine functions thereby controlling osteogenesis and hematopoiesis. While some functions of BMAT may be beneficial for metabolic adaptation and bone homeostasis, respectively, most findings assign bone fat a detrimental role during regenerative processes, such as hematopoiesis and osteogenesis. Thus, an improved understanding of the biological mechanisms leading to formation of BMAT, its molecular characteristics, and its physiological role in the bone marrow niche is warranted. Here we review the current understanding of BMAT biology and its potential implications for health and the development of pathological conditions.
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20
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Firth EC, Gamble GD, Cornish J, Vickers MH. Neonatal leptin treatment reverses the bone-suppressive effects of maternal undernutrition in adult rat offspring. Sci Rep 2017; 7:7686. [PMID: 28794412 PMCID: PMC5550441 DOI: 10.1038/s41598-017-07500-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/29/2017] [Indexed: 11/19/2022] Open
Abstract
Alterations in the early life environment, including maternal undernutrition (UN) during pregnancy, can lead to increased risk of metabolic and cardiovascular disorders in offspring. Leptin treatment of neonates born to UN rats reverses the programmed metabolic phenotype, but the possible benefits of this treatment on bone tissue have not been defined. We describe for the first time the effects of neonatal leptin treatment on bone in adult offspring following maternal UN. Offspring from either UN or ad libitum-fed (AD) rats were treated with either saline or leptin (2.5 µg/ g.d on postnatal days (D)3–13) and were fed either a chow or high fat (HF) diet from weaning until study completion at D170. Analysis of micro-tomographic data of the left femur showed highly significant effects of UN on cortical and trabecular bone tissue indices, contributing to inferior microstructure and bone strength, almost all of which were reversed by early leptin life treatment. The HF fat diet negatively affected trabecular bone tissue, but the effects of only trabecular separation and number were reversed by leptin treatment. The negative effects of maternal UN on skeletal health in adult offspring might be prevented or attenuated by various interventions including leptin. Establishment of a minimal efficacious leptin dose warrants further study.
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Affiliation(s)
- Elwyn C Firth
- Liggins Institute, University of Auckland, Auckland, New Zealand. .,Department of Exercise Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
| | - Greg D Gamble
- Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Jillian Cornish
- Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Mark H Vickers
- Liggins Institute, University of Auckland, Auckland, New Zealand
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21
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Hamrick MW. Role of the Cytokine-like Hormone Leptin in Muscle-bone Crosstalk with Aging. J Bone Metab 2017; 24:1-8. [PMID: 28326295 PMCID: PMC5357607 DOI: 10.11005/jbm.2017.24.1.1] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 12/20/2016] [Indexed: 12/14/2022] Open
Abstract
The cytokine-like hormone leptin is a classic adipokine that is secreted by adipocytes, increases with weight gain, and decreases with weight loss. Additional studies have, however, shown that leptin is also produced by skeletal muscle, and leptin receptors are abundant in both skeletal muscle and bone-derived mesenchymal (stromal) stem cells. These findings suggest that leptin may play an important role in muscle-bone crosstalk. Leptin treatment in vitro increases the expression of myogenic genes in primary myoblasts, and leptin treatment in vivo increases the expression of microRNAs involved in myogenesis. Bone marrow adipogenesis is associated with low bone mass in humans and rodents, and leptin can reduce marrow adipogenesis centrally through its receptors in the hypothalamus as well as directly via its receptors in bone marrow stem cells. Yet, central leptin resistance can increase with age, and low circulating levels of leptin have been observed among the frail elderly. Thus, aging appears to significantly alter leptin-mediated crosstalk among various organs and tissues. Aging is associated with bone loss and muscle atrophy, contributing to frailty, postural instability, and the incidence of falls. Therapeutic interventions such as protein and amino acid supplementation that can increase muscle mass and muscle-derived leptin may have multiple benefits for the elderly that can potentially reduce the incidence of falls and fractures.
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Affiliation(s)
- Mark W. Hamrick
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
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22
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Binks S, Dobson R. Risk Factors, Epidemiology and Treatment Strategies for Metabolic Bone Disease in Patients with Neurological Disease. Curr Osteoporos Rep 2016; 14:199-210. [PMID: 27525980 DOI: 10.1007/s11914-016-0320-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Metabolic bone disease is a major public health concern, especially when it manifests as hip fracture which carries significant morbidity and mortality. Individuals with neurological disease are at higher risk of osteopenia, osteoporosis and fragility fracture compared to age-matched controls, yet this is under-appreciated by these patients. Clinician attention to this topic is therefore of importance and should address the bone health of men as well as women, a group in whom it may be an under-recognised problem. Evidence for optimal management of bone health in neurological disease remains to be defined, but a growing literature provides some useful guidance. This review focuses on two conditions, multiple sclerosis and Parkinson's disease, where research has been active over recent years. In neuroinflammation, shared immunological pathways between bone and brain are a current domain of interest and it will be intriguing to interrogate the action of emerging immunotherapies on these dual compartments.
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Affiliation(s)
- S Binks
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - R Dobson
- Blizard Institute, Queen Mary University, 4 Newark St, London, E1 2AT, UK.
- St Georges Hospital, Blackshaw Rd, London, SW17 0QT, UK.
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23
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Metzger CE, Baek K, Swift SN, De Souza MJ, Bloomfield SA. Exercise during energy restriction mitigates bone loss but not alterations in estrogen status or metabolic hormones. Osteoporos Int 2016; 27:2755-2764. [PMID: 27129456 DOI: 10.1007/s00198-016-3590-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 04/04/2016] [Indexed: 01/26/2023]
Abstract
UNLABELLED Energy restriction causes bone loss, increasing stress fracture risk. The impact of exercise during energy restriction on bone and endocrine factors is examined. Exercise with energy restriction did not influence endocrine factors, but did mitigate some bone loss seen with energy restriction in sedentary rats. INTRODUCTION Chronic dietary energy restriction (ER) leads to bone loss and increased fracture risk. Strictly controlled trials of long-term ER with and without vigorous exercise are required to determine whether exercise loading can counterbalance ER-induced bone loss. The aim of this current project is to elucidate the impact of exercise and ER on bone mass, estrogen status, and metabolic hormones. METHODS Twenty-four virgin female Sprague-Dawley rats (n = 8/group) were divided into three groups-ad libitum fed + exercise (Adlib + EX), 40 % energy restricted + exercise (ER + EX), and 40 % energy restricted + sedentary (ER + SED). Energy availability between ER groups was equal. Treadmill running was performed 4 days/week at 70 % VO2max for 12 weeks. RESULTS Fat and lean mass and areal bone mineral density (aBMD) were lower after 12 weeks (p < 0.05) for ER + EX vs Adlib + EX, but ER + EX aBMD was higher than ER + SED (p < 0.0001). Serum leptin and a urinary estrogen metabolite, estrone-1-glucuronide (E1G), were lower at week 12 (p = 0.0002) with ER, with no impact of exercise. Serum insulin-like growth factor I (IGF-I) declined (p = 0.02) from baseline to week 12 in both ER groups. ER + EX exhibited higher cortical volumetric bone mineral density (vBMD) at the midshaft tibia (p = 0.006) vs ER + SED. CONCLUSION Exercise during ER mitigated some, but not all, of the bone loss observed in sedentary ER rats, but had little impact on changes in urinary E1G and serum IGF-I and leptin. These data highlight the importance of both adequate energy intake and the mechanical loading of exercise in maintaining bone mass.
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Affiliation(s)
- C E Metzger
- Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA
| | - K Baek
- Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA
- Department of Pharmacology, College of Dentistry and Research of Oral Science, Gangneung-Wonju National University, Gangwondo, Korea
| | - S N Swift
- Division of Dietary Supplement Programs, Federal Drug Administration, College Park, MD, USA
- Department of Nutrition & Food Science, Texas A&M University, College Station, TX, USA
| | - M J De Souza
- Departments of Kinesiology and Physiology, The Pennsylvania State University, State College, PA, USA
| | - S A Bloomfield
- Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA.
- Departments of Kinesiology and Physiology, The Pennsylvania State University, State College, PA, USA.
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24
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Kaczmarek MM, Mendoza T, Kozak LP. Lactation undernutrition leads to multigenerational molecular programming of hypothalamic gene networks controlling reproduction. BMC Genomics 2016; 17:333. [PMID: 27146259 PMCID: PMC4857247 DOI: 10.1186/s12864-016-2615-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 04/08/2016] [Indexed: 12/22/2022] Open
Abstract
Background Reproductive success is dependent on development of hypothalamic circuits involving many hormonal systems working in concert to regulate gonadal function and sexual behavior. The timing of pubertal initiation and progression in mammals is likely influenced by the nutritional and metabolic state, leading us to the hypothesis that transient malnutrition experienced at critical times during development may perturb pubertal progression through successive generations. To test this hypothesis we have utilized a mouse model of undernutrition during suckling by exposing lactating mothers to undernutrition. Results Using a combination of transcriptomic and biological approaches, we demonstrate that molecular programming of hypothalamus may perturb gender specific phenotypes across generations that are dependent on the nutritional environment of the lactation period. Lactation undernutrition in first (F1) generation offspring affected body composition, reproductive performance parameters and influenced the expression of genes responsible for hypothalamic neural circuits controlling reproductive function of both sexes. Strikingly, F2 offspring showed phenotypes similar to F1 progeny; however, they were sex and parental nutritional history specific. Here, we showed that deregulated expression of genes involved in kisspeptin signaling within the hypothalamus is strongly associated with a delay in the attainment of puberty in F1 and F2 male and female offspring. Conclusion The early developmental plasticity of hypothalamus when challenged with undernutrition during postnatal development not only leads to altered expression of genes controlling hypothalamic neural circuits, altered body composition, delayed puberty and disturbed reproductive performance in F1 progeny, but also affects F2 offspring, depending on parental malnutrition history and in sexually dimorphic manner. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2615-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Monika M Kaczmarek
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
| | - Tamra Mendoza
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Leslie P Kozak
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
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25
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Cruz Grecco Teixeira MB, Martins GM, Miranda-Rodrigues M, De Araújo IF, Oliveira R, Brum PC, Azevedo Gouveia CH. Lack of α2C-Adrenoceptor Results in Contrasting Phenotypes of Long Bones and Vertebra and Prevents the Thyrotoxicosis-Induced Osteopenia. PLoS One 2016; 11:e0146795. [PMID: 26815679 PMCID: PMC4729682 DOI: 10.1371/journal.pone.0146795] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 12/21/2015] [Indexed: 12/26/2022] Open
Abstract
A series of studies have demonstrated that activation of the sympathetic nervous system (SNS) causes osteopenia via β2-adrenoceptor (β2-AR) signaling. However, in a recent study, we found an unexpected and generalized phenotype of high bone mass in female mice with chronic sympathetic hyperactivity, due to double gene inactivation of adrenoceptors that negatively regulate norepinephrine release, α2A-and α2C-AR (α2A/2C-AR-/-). These findings suggest that β2-AR is not the single adrenoceptor involved in bone turnover regulation and show that α2-AR signaling may also mediate the SNS actions in the skeleton. In addition, we found that α2A/2C-AR-/- animals are resistant to the thyrotoxicosis-induced osteopenia, suggesting that thyroid hormone (TH), when in supraphysiological levels, interacts with the SNS to control bone mass and structure, and that this interaction may also involve α2-AR signaling. In the present study, to further investigate these hypotheses and to discriminate the roles of α2-AR subtypes, we have evaluated the bone phenotype of mice with the single gene inactivation of α2C-AR subtype, which mRNA expression was previously shown to be down regulated by triiodothyronine (T3). A cohort of 30 day-old female α2CAR-/- mice and their wild-type (WT) controls were treated with a supraphysiological dose of T3 for 30 or 90 days, which induced a thyrotoxic state in both mouse lineages. The micro-computed tomographic (μCT) analysis showed that α2C-AR-/- mice present lower trabecular bone volume (BV/TV) and number (Tb.N), and increased trabecular separation (Tb.Sp) in the femur compared with WT mice; which was accompanied by decreased bone strength (determined by the three-point bending test) in the femur and tibia. The opposite was observed in the vertebra, where α2C-AR-/- mice show increased BV/TV, Tb.N and trabecular thickness (Tb.Th), and decreased Tb.Sp, compared with WT animals. In spite of the contrasting bone phenotypes of the femur and L5, thyrotoxicosis negatively regulated most of the micro architectural features of the trabecular bone in both skeletal sites of WT, but not of α2C-AR-/- mice. T3 treatment also decreased biomechanical properties (maximum load and ultimate load) in the femur and tibia of WT, but not of knockout mice. The mRNA expression of osteocalcin, a marker of mature osteoblasts, and tartrate-resistant acid phosphatase, which is expressed by osteoclasts and is involved in collagen degradation, was increased by T3 treatment only in WT, and not in α2C-AR-/- mice. Altogether, these findings suggest that α2C-AR subtype mediates the effects of the SNS in the bone in a skeletal site-dependent manner, and that thyrotoxicosis depends on α2C-AR signaling to promote bone loss, which sustains the hypothesis of a TH-SNS interaction to modulate bone remodeling and structure.
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Affiliation(s)
| | - Gisele Miyamura Martins
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | | | - Patrícia Chakur Brum
- Departament of Biodinamic of Human Body Moviment, School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil
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Coleman SK, Rebalka IA, D’Souza DM, Hawke TJ. Skeletal muscle as a therapeutic target for delaying type 1 diabetic complications. World J Diabetes 2015; 6:1323-1336. [PMID: 26674848 PMCID: PMC4673386 DOI: 10.4239/wjd.v6.i17.1323] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 10/01/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease targeting the pancreatic beta-cells and rendering the person hypoinsulinemic and hyperglycemic. Despite exogenous insulin therapy, individuals with T1DM will invariably develop long-term complications such as blindness, kidney failure and cardiovascular disease. Though often overlooked, skeletal muscle is also adversely affected in T1DM, with both physical and metabolic derangements reported. As the largest metabolic organ in the body, impairments to skeletal muscle health in T1DM would impact insulin sensitivity, glucose/lipid disposal and basal metabolic rate and thus affect the ability of persons with T1DM to manage their disease. In this review, we discuss the impact of T1DM on skeletal muscle health with a particular focus on the proposed mechanisms involved. We then identify and discuss established and potential adjuvant therapies which, in association with insulin therapy, would improve the health of skeletal muscle in those with T1DM and thereby improve disease management- ultimately delaying the onset and severity of other long-term diabetic complications.
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Preliminary Characterization of a Leptin Receptor Knockout Rat Created by CRISPR/Cas9 System. Sci Rep 2015; 5:15942. [PMID: 26537785 PMCID: PMC4633582 DOI: 10.1038/srep15942] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 09/29/2015] [Indexed: 12/28/2022] Open
Abstract
Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions. In addition, the leptin receptor knockout rats show a significant decrease in bone volume and bone mineral density of the femur compared with their wild-type littermates. Our model has rescued some deficiency of the existing rodent models, such as the transient hyperglycemia of db/db mice in the C57BL/6J genetic background and the delayed onset of glucose intolerance in the Zucker rats, and it is proven to be a useful animal model for biomedical and pharmacological research on obesity and diabetes.
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Abstract
Obesity and osteoporosis are two of the most common chronic disorders of the 21st century. Both are accompanied by significant morbidity. The only place in the mammalian organism where bone and fat lie adjacent to each other is in the bone marrow. Marrow adipose tissue is a dynamic depot that probably exists as both constitutive and regulated compartments. Adipocytes secrete cytokines and adipokines that either stimulate or inhibit adjacent osteoblasts. The relationship of marrow adipose tissue to other fat depots is complex and might play very distinct parts in modulation of metabolic homoeostasis, haemopoiesis, and osteogenesis. Understanding of the relationship between bone and fat cells that arise from the same progenitor within the bone marrow niche provides insight into the pathophysiology of age-related osteoporosis, diabetes, and obesity.
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Affiliation(s)
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Scarborough, ME 04074, USA
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Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev 2014; 33:527-43. [PMID: 24398857 PMCID: PMC4154371 DOI: 10.1007/s10555-013-9484-y] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease.
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Affiliation(s)
- Aimalie L. Hardaway
- Department of Pharmacology, Wayne State University School of, Medicine, 540 E. Canfield, Rm 6304, Detroit, MI 48201, USA
- Karmanos Cancer Institute, Wayne State University School of, Medicine, Detroit, MI 48201, USA
| | - Mackenzie K. Herroon
- Department of Pharmacology, Wayne State University School of, Medicine, 540 E. Canfield, Rm 6304, Detroit, MI 48201, USA
| | - Erandi Rajagurubandara
- Department of Pharmacology, Wayne State University School of, Medicine, 540 E. Canfield, Rm 6304, Detroit, MI 48201, USA
| | - Izabela Podgorski
- Department of Pharmacology, Wayne State University School of, Medicine, 540 E. Canfield, Rm 6304, Detroit, MI 48201, USA
- Karmanos Cancer Institute, Wayne State University School of, Medicine, Detroit, MI 48201, USA
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Absence of functional leptin receptor isoforms in the POUND (Lepr(db/lb)) mouse is associated with muscle atrophy and altered myoblast proliferation and differentiation. PLoS One 2013; 8:e72330. [PMID: 23967295 PMCID: PMC3743798 DOI: 10.1371/journal.pone.0072330] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 07/08/2013] [Indexed: 12/31/2022] Open
Abstract
Objective Leptin receptors are abundant in human skeletal muscle, but the role of leptin in muscle growth, development and aging is not well understood. Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Leprdb/lb) to determine the role of leptin in skeletal muscle. Methods and Findings Skeletal muscle mass and fiber diameters were examined in POUND mice, and primary myoblast cultures were used to determine the effects of altered leptin signaling on myoblast proliferation and differentiation. ELISA assays, integrated pathway analysis of mRNA microarrays, and reverse phase protein analysis were performed to identify signaling pathways impacted by leptin receptor deficiency. Results show that skeletal muscle mass and fiber diameter are reduced 30–40% in POUND mice relative to wild-type controls. Primary myoblast cultures demonstrate decreased proliferation and decreased expression of both MyoD and myogenin in POUND mice compared to normal mice. Leptin treatment increased proliferation in primary myoblasts from muscles of both adult (12 months) and aged (24 months) wild-type mice, and leptin increased expression of MyoD and myogenin in aged primary myoblasts. ELISA assays and protein arrays revealed altered expression of molecules associated with the IGF-1/Akt and MAPK/MEK signaling pathways in muscle from the hindlimbs of mice lacking functional leptin receptors. Conclusion These data support the hypothesis that the adipokine leptin is a key factor important for the regulation of skeletal muscle mass, and that leptin can act directly on its receptors in peripheral tissues to regulate cell proliferation and differentiation.
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Chapnik N, Solomon G, Genzer Y, Miskin R, Gertler A, Froy O. A superactive leptin antagonist alters metabolism and locomotion in high-leptin mice. J Endocrinol 2013; 217:283-90. [PMID: 23482705 DOI: 10.1530/joe-13-0033] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Transgenic alpha murine urokinase-type plasminogen activator (αMUPA) mice are resistant to obesity and their locomotor activity is altered. As these mice have high leptin levels, our objective was to test whether leptin is responsible for these characteristics. αMUPA, their genetic background control (FVB/N), and C57BL mice were injected s.c. every other day with 20 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 6 weeks. We tested the effect of PEG-SMLA on body weight, locomotion, and bone health. The antagonist led to a rapid increase in body weight and subsequent insulin resistance in all treated mice. Food intake of PEG-SMLA-injected animals increased during the initial period of the experiment but then declined to a similar level to that of the control animals. Interestingly, αMUPA mice were found to have reduced bone volume (BV) than FVB/N mice, although PEG-SMLA increased bone mass in both strains. In addition, PEG-SMLA led to disrupted locomotor activity and increased corticosterone levels in C57BL but decreased levels in αMUPA or FVB/N mice. These results suggest that leptin is responsible for the lean phenotype and reduced BV in αMUPA mice; leptin affects corticosterone levels in mice in a strain-specific manner; and leptin alters locomotor activity, a behavior determined by the central circadian clock.
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Affiliation(s)
- Nava Chapnik
- Robert H Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel
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Devlin MJ, Grasemann C, Cloutier AM, Louis L, Alm C, Palmert MR, Bouxsein ML. Maternal perinatal diet induces developmental programming of bone architecture. J Endocrinol 2013; 217:69-81. [PMID: 23503967 PMCID: PMC3792707 DOI: 10.1530/joe-12-0403] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.
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Affiliation(s)
- M J Devlin
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
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33
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Fazeli PK, Horowitz MC, MacDougald OA, Scheller EL, Rodeheffer MS, Rosen CJ, Klibanski A. Marrow fat and bone--new perspectives. J Clin Endocrinol Metab 2013; 98:935-45. [PMID: 23393168 PMCID: PMC3590487 DOI: 10.1210/jc.2012-3634] [Citation(s) in RCA: 286] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CONTEXT There is growing interest in the relationship between bone mineral density, bone strength, and fat depots. Marrow adipose tissue, a well-established component of the marrow environment, is metabolically distinct from peripheral fat depots, but its functional significance is unknown. OBJECTIVE In this review, we discuss animal and human data linking the marrow adipose tissue depot to parameters of bone density and integrity as well as the potential significance of marrow adipose tissue in metabolic diseases associated with bone loss, including type 1 diabetes mellitus and anorexia nervosa. Potential hormonal determinants of marrow adipose tissue are also discussed. CONCLUSIONS We conclude that whereas most animal and human data demonstrate an inverse association between marrow adipose tissue and measures of bone density and strength, understanding the functional significance of marrow adipose tissue and its hormonal determinants will be critical to better understanding its role in skeletal integrity and the role of marrow adipose tissue in the pathophysiology of bone loss.
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Affiliation(s)
- Pouneh K Fazeli
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Turner RT, Kalra SP, Wong CP, Philbrick KA, Lindenmaier LB, Boghossian S, Iwaniec UT. Peripheral leptin regulates bone formation. J Bone Miner Res 2013; 28:22-34. [PMID: 22887758 PMCID: PMC3527690 DOI: 10.1002/jbmr.1734] [Citation(s) in RCA: 187] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Revised: 06/30/2012] [Accepted: 07/16/2012] [Indexed: 12/15/2022]
Abstract
Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild-type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice, and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity.
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Affiliation(s)
- Russell T. Turner
- Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, 97331, USA
| | - Satya P. Kalra
- Department of Neuroscience, University of Florida McKnight Brain Institute, Gainesville, FL, 32610, USA
| | - Carmen P. Wong
- Molecular and Cellular Nutrition Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, 97331, USA
| | - Kenneth A. Philbrick
- Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, 97331, USA
| | - Laurence B. Lindenmaier
- Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, 97331, USA
| | - Stephane Boghossian
- Department of Neuroscience, University of Florida McKnight Brain Institute, Gainesville, FL, 32610, USA
| | - Urszula T. Iwaniec
- Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, 97331, USA
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Vaira S, Yang C, McCoy A, Keys K, Xue S, Weinstein EJ, Novack DV, Cui X. Creation and preliminary characterization of a leptin knockout rat. Endocrinology 2012; 153:5622-8. [PMID: 22948215 PMCID: PMC3473197 DOI: 10.1210/en.2012-1462] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Leptin, a cytokine-like hormone secreted mainly by adipocytes, regulates various pathways centered on food intake and energy expenditure, including insulin sensitivity, fertility, immune system, and bone metabolism. Here, using zinc finger nuclease technology, we created the first leptin knockout rat. Homozygous leptin null rats are obese with significantly higher serum cholesterol, triglyceride, and insulin levels than wild-type controls. Neither gender produced offspring despite of repeated attempts. The leptin knockout rats also have depressed immune system. In addition, examination by microcomputed tomography of the femurs of the leptin null rats shows a significant increase in both trabecular bone mineral density and bone volume of the femur compared with wild-type littermates. Our model should be useful for many different fields of studies, such as obesity, diabetes, and bone metabolism-related illnesses.
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Affiliation(s)
- Sergio Vaira
- Sigma Advanced Genetic Engineering Labs, Sigma-Aldrich Corp., St. Louis, Missouri 63146, USA
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36
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Batista S, Teter B, Sequeira K, Josyula S, Hoogs M, Ramanathan M, Benedict RHB, Weinstock-Guttman B. Cognitive impairment is associated with reduced bone mass in multiple sclerosis. Mult Scler 2012; 18:1459-65. [PMID: 22419674 DOI: 10.1177/1352458512440206] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Multiple sclerosis (MS) has been associated with reduced bone mineral density (BMD), yet the underlying causes are not fully known. The recent discovery that bone homeostasis is directly regulated by the brain led us to hypothesize that it may be impaired by MS pathology. As cognitive impairment (CI) is a well-documented correlate of MS-related brain pathology, we tested the hypothesis that it is associated with reduced BMD. OBJECTIVE We aimed to determine if CI is associated with reduced BMD in patients with MS. METHODS We retrospectively studied the medical records of 56 patients with MS, ≤50 years old, with Expanded Disability Status Scale score ≤4.5 and with dual X-ray absorptiometry (DEXA) BMD measurement within 1 year of neuropsychological testing with a standard battery (MACFIMS). RESULTS In total, 23 (41.1%) MS patients had osteopenia or osteoporosis. Mean femur BMD was significantly lower in patients with MS with CI (0.89±0.12 g/cm(2)) compared with intact patients (0.99±0.17 g/cm(2), p=0.009). In the cognitively impaired group, 59.3% had either osteopenia or osteoporosis, compared with 24.1% in the non-cognitively impaired group (odds ratio=4.57, p=0.008). CONCLUSION CI is associated with reduced BMD in patients with MS, suggesting that central mechanisms involved in bone homeostasis may be directly impaired by MS-related inflammatory and neurodegenerative processes.
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Affiliation(s)
- Sonia Batista
- Department of Neurology, Hospitais da Universidade de Coimbra, Portugal. R00 HD060765
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Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone 2012; 50:534-9. [PMID: 21757043 PMCID: PMC3197966 DOI: 10.1016/j.bone.2011.06.032] [Citation(s) in RCA: 132] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 06/24/2011] [Accepted: 06/25/2011] [Indexed: 12/25/2022]
Abstract
Recent advances in understanding the role of bone in the systemic regulation of energy metabolism indicate that bone marrow cells, adipocytes and osteoblasts, are involved in this process. Marrow adipocytes store significant quantities of fat and produce adipokines, leptin and adiponectin, which are known for their role in the regulation of energy metabolism, whereas osteoblasts produce osteocalcin, a bone-specific hormone that has a potential to regulate insulin production in the pancreas and adiponectin production in fat tissue. Both osteoblasts and marrow adipocytes express insulin receptor and respond to insulin-sensitizing anti-diabetic TZDs in a manner, which tightly links bone with the energy metabolism system. Metabolic profile of marrow fat resembles that of both, white and brown fat, which is reflected by its plasticity in acquiring different functions including maintenance of bone micro-environment. Marrow fat responds to physiologic and pathologic changes in energy metabolism status by changing volume and metabolic activity. This review summarizes available information on the metabolic function of marrow fat and provides hypothesis that this fat depot may acquire multiple roles depending on the local and perhaps systemic demands. These functions may include a role in bone energy maintenance and endocrine activities to serve osteogenesis during bone remodeling and bone healing.
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Affiliation(s)
- Beata Lecka-Czernik
- Department of Orthopaedic Surgery, University of Toledo Health Sciences Campus, Toledo, OH 43614, USA.
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38
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Devlin MJ. Why does starvation make bones fat? Am J Hum Biol 2011; 23:577-85. [PMID: 21793093 DOI: 10.1002/ajhb.21202] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 04/27/2011] [Accepted: 05/30/2011] [Indexed: 12/20/2022] Open
Abstract
Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance.
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Affiliation(s)
- Maureen J Devlin
- Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
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Iwaniec UT, Boghossian S, Trevisiol CH, Wronski TJ, Turner RT, Kalra SP. Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats. J Bone Miner Res 2011; 26:1506-16. [PMID: 21328617 PMCID: PMC3129999 DOI: 10.1002/jbmr.365] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Hypothalamic leptin gene therapy normalizes the mosaic skeletal phenotype of leptin-deficient ob/ob mice. However, it is not clear whether increased hypothalamic leptin alters bone metabolism in animals already producing the hormone. The objective of this study was to evaluate the long duration effects of recombinant adeno-associated virus-rat leptin (rAAV-Lep) hypothalamic gene therapy on weight gain and bone metabolism in growing and skeletally mature leptin-replete female Sprague-Dawley rats. Rats were either unoperated or implanted with cannulas in the third ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained on standard rat chow fed ad libitum for either 5 or 10 weeks (starting at 3 months of age) or 18 weeks (starting at 9 months of age). Tibias, femurs, or lumbar vertebrae were analyzed by micro-computed tomography and/or histomorphometry. In comparison with age-matched rAAV-GFP rats, rAAV-Lep rats maintained a lower body weight for the duration of studies. At 5 weeks after vector administration, rAAV-Lep rats had lower cancellous bone volume and bone marrow adiposity but higher osteoblast perimeter compared with nonoperated controls. However, these values did not differ between the two groups at 10 weeks after vector administration. Differences in cancellous bone volume and architecture were not detected between the rAAV-Lep and rAAV-GFP groups at either time point. Also, rAAV-Lep had no negative effects on bone in the 9-month-old skeletally mature rats at 18 weeks after vector administration. We hypothesize that the transient reductions in bone mass and bone marrow adiposity at 5 weeks after vector administration were due to hypothalamic surgery. We conclude that increased hypothalamic leptin, sufficient to prevent weight gain, has minimal specific effects (rAAV-Lep versus rAAV-GFP) on bone metabolism in normal female rats.
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Affiliation(s)
- Urszula T Iwaniec
- Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA.
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Sherk VD, Malone SP, Bemben MG, Knehans AW, Palmer IJ, Bemben DA. Leptin, fat mass, and bone mineral density in healthy pre- and postmenopausal women. J Clin Densitom 2011; 14:321-5. [PMID: 21600824 DOI: 10.1016/j.jocd.2011.03.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Revised: 02/23/2011] [Accepted: 03/30/2011] [Indexed: 12/31/2022]
Abstract
The purpose was to examine relationships between age, fat mass, and bone mineral density (BMD) with resting leptin levels in premenopausal and postmenopausal women. Young (aged 18-30 yr, n=30) and estrogen-deficient postmenopausal (aged 55-75 yr, n=43) women were recruited. Total body and segmental fat mass and bone-free lean body mass (BFLBM) and total body, lumbar spine, and proximal femur BMD were assessed using dual-energy X-ray absorptiometry. Serum-resting, fasted leptin levels were measured by Immunoradiometric Assay (IRMA), and leptin-to-fat mass ratios were calculated. Young and older women had similar amounts of BFLBM, but older women had greater (p<0.05) amounts of fat mass and 35% higher leptin levels. Age differences in leptin concentrations were no longer significant after controlling for fat mass. Older women had significantly (p<0.05) lower hip BMD values. Age was negatively related (r=-0.29, p<0.05) to leptin:trunk fat ratio. Increases in fat mass, not menopause per se, contributes to higher leptin levels in older women. Relationships between leptin and BMD may be age dependent.
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Affiliation(s)
- Vanessa D Sherk
- Department of Health and Exercise Science, University of Oklahoma, Norman, OK, USA
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Hasan TF, Hasan H. Anorexia nervosa: a unified neurological perspective. Int J Med Sci 2011; 8:679-703. [PMID: 22135615 PMCID: PMC3204438 DOI: 10.7150/ijms.8.679] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 09/19/2011] [Indexed: 12/20/2022] Open
Abstract
The roles of corticotrophin-releasing factor (CRF), opioid peptides, leptin and ghrelin in anorexia nervosa (AN) were discussed in this paper. CRF is the key mediator of the hypothalamo-pituitary-adrenal (HPA) axis and also acts at various other parts of the brain, such as the limbic system and the peripheral nervous system. CRF action is mediated through the CRF1 and CRF2 receptors, with both HPA axis-dependent and HPA axis-independent actions, where the latter shows nil involvement of the autonomic nervous system. CRF1 receptors mediate both the HPA axis-dependent and independent pathways through CRF, while the CRF2 receptors exclusively mediate the HPA axis-independent pathways through urocortin. Opioid peptides are involved in the adaptation and regulation of energy intake and utilization through reward-related behavior. Opioids play a role in the addictive component of AN, as described by the "auto-addiction opioids theory". Their interactions have demonstrated the psychological aspect of AN and have shown to prevent the functioning of the physiological homeostasis. Important opioids involved are β-lipotropin, β-endorphin and dynorphin, which interact with both µ and κ opioids receptors to regulate reward-mediated behavior and describe the higher incidence of AN seen in females. Moreover, ghrelin is known as the "hunger" hormone and helps stimulate growth hormone (GH) and hepatic insulin-like-growth-factor-1(IGF-1), maintaining anabolism and preserving a lean body mass. In AN, high levels of GH due to GH resistance along with low levels of IGF-1 are observed. Leptin plays a role in suppressing appetite through the inhibition of neuropeptide Y gene. Moreover, the CRF, opioid, leptin and ghrelin mechanisms operate collectively at the HPA axis and express the physiological and psychological components of AN. Fear conditioning is an intricate learning process occurring at the level of the hippocampus, amygdala, lateral septum and the dorsal raphe by involving three distinct pathways, the HPA axis-independent pathway, hypercortisolemia and ghrelin. Opioids mediate CRF through noradrenergic stimulation in association with the locus coeruleus. Furthermore, CRF's inhibitory effect on gonadotropin releasing hormone can be further explained by the direct relationship seen between CRF and opioids. Low levels of gonadotropin have been demonstrated in AN where only estrogen has shown to mediate energy intake. In addition, estrogen is involved in regulating µ receptor concentrations, but in turn both CRF and opioids regulate estrogen. Moreover, opioids and leptin are both an effect of AN, while many studies have demonstrated a causal relationship between CRF and anorexic behavior. Moreover, leptin, estrogen and ghrelin play a role as predictors of survival in starvation. Since both leptin and estrogen are associated with higher levels of bone marrow fat they represent a longer survival than those who favor the ghrelin pathway. Future studies should consider cohort studies involving prepubertal males and females with high CRF. This would help prevent the extrapolation of results from studies on mice and draw more meaningful conclusions in humans. Studies should also consider these mechanisms in post-AN patients, as well as look into what predisposes certain individuals to develop AN. Finally, due to its complex pathogenesis the treatment of AN should focus on both the pharmacological and behavioral perspectives.
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Devlin MJ, Cloutier AM, Thomas NA, Panus DA, Lotinun S, Pinz I, Baron R, Rosen CJ, Bouxsein ML. Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. J Bone Miner Res 2010; 25:2078-88. [PMID: 20229598 PMCID: PMC3127399 DOI: 10.1002/jbmr.82] [Citation(s) in RCA: 253] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Revised: 02/11/2010] [Accepted: 03/04/2010] [Indexed: 12/12/2022]
Abstract
The effects of caloric restriction (CR) on the skeleton are well studied in adult rodents and include lower cortical bone mass but higher trabecular bone volume. Much less is known about how CR affects bone mass in young, rapidly growing animals. This is an important problem because low caloric intake during skeletal acquisition in humans, as in anorexia nervosa, is associated with low bone mass, increased fracture risk, and osteoporosis in adulthood. To explore this question, we tested the effect of caloric restriction on bone mass and microarchitecture during rapid skeletal growth in young mice. At 3 weeks of age, we weaned male C57Bl/6J mice onto 30% caloric restriction (10% kcal/fat) or normal diet (10% kcal/fat). Outcomes at 6 (n = 4/group) and 12 weeks of age (n = 8/group) included body mass, femur length, serum leptin and insulin-like growth factor 1 (IGF-1) values, whole-body bone mineral density (WBBMD, g/cm(2)), cortical and trabecular bone architecture at the midshaft and distal femur, bone formation and cellularity, and marrow fat measurement. Compared with the normal diet, CR mice had 52% and 88% lower serum leptin and 33% and 39% lower serum IGF-1 at 6 and 12 weeks of age (p < .05 for all). CR mice were smaller, with lower bone mineral density, trabecular, and cortical bone properties. Bone-formation indices were lower, whereas bone-resorption indices were higher (p < .01 for all) in CR versus normal diet mice. Despite having lower percent of body fat, bone marrow adiposity was elevated dramatically in CR versus normal diet mice (p < .05). Thus we conclude that caloric restriction in young, growing mice is associated with impaired skeletal acquisition, low leptin and IGF-1 levels, and high marrow adiposity. These results support the hypothesis that caloric restriction during rapid skeletal growth is deleterious to cortical and trabecular bone mass and architecture, in contrast to potential skeletal benefits of CR in aging animals.
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Affiliation(s)
- Maureen J Devlin
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
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Hamrick MW, Herberg S, Arounleut P, He HZ, Shiver A, Qi RQ, Zhou L, Isales CM, Mi QS. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice. Biochem Biophys Res Commun 2010; 400:379-83. [PMID: 20800581 DOI: 10.1016/j.bbrc.2010.08.079] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Accepted: 08/23/2010] [Indexed: 02/05/2023]
Abstract
Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin may be able to reverse muscle atrophy and alter the expression of atrophy-related miRNAs in aging skeletal muscle.
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Affiliation(s)
- Mark W Hamrick
- Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
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Impaired perinatal growth and longevity: a life history perspective. Curr Gerontol Geriatr Res 2009:608740. [PMID: 19746180 PMCID: PMC2738951 DOI: 10.1155/2009/608740] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2009] [Accepted: 07/01/2009] [Indexed: 01/21/2023] Open
Abstract
Life history theory proposes that early-life cues induce highly integrated responses in traits associated with energy partitioning, maturation, reproduction, and aging such that the individual phenotype is adaptively more appropriate to the anticipated environment. Thus, maternal and/or neonatally derived nutritional or endocrine cues suggesting a threatening environment may favour early growth and reproduction over investment in tissue reserve and repair capacity. These may directly affect longevity, as well as prioritise insulin resistance and capacity for fat storage, thereby increasing susceptibility to metabolic dysfunction and obesity. These shifts in developmental trajectory are associated with long-term expression changes in specific genes, some of which may be underpinned by epigenetic processes. This normative process of developmental plasticity may prove to be maladaptive in human environments in transition towards low extrinsic mortality and energy-dense nutrition, leading to the development of an inappropriate phenotype with decreased potential for longevity and/or increased susceptibility to metabolic disease.
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Pre- and postnatal nutritional histories influence reproductive maturation and ovarian function in the rat. PLoS One 2009; 4:e6744. [PMID: 19707592 PMCID: PMC2727050 DOI: 10.1371/journal.pone.0006744] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Accepted: 07/27/2009] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND While prepubertal nutritional influences appear to play a role in sexual maturation, there is a need to clarify the potential contributions of maternal and childhood influences in setting the tempo of reproductive maturation. In the present study we employed an established model of nutritional programming to evaluate the relative influences of prenatal and postnatal nutrition on growth and ovarian function in female offspring. METHODS Pregnant Wistar rats were fed either a calorie-restricted diet, a high fat diet, or a control diet during pregnancy and/or lactation. Offspring then were fed either a control or a high fat diet from the time of weaning to adulthood. Pubertal age was monitored and blood samples collected in adulthood for endocrine analyses. RESULTS We report that in the female rat, pubertal timing and subsequent ovarian function is influenced by the animal's nutritional status in utero, with both maternal caloric restriction and maternal high fat nutrition resulting in early pubertal onset. Depending on the offspring's nutritional history during the prenatal and lactational periods, subsequent nutrition and body weight gain did not further influence offspring reproductive tempo, which was dominated by the effect of prenatal nutrition. Whereas maternal calorie restriction leads to early pubertal onset, it also leads to a reduction in adult progesterone levels later in life. In contrast, we found that maternal high fat feeding which also induces early maturation in offspring was associated with elevated progesterone concentrations. CONCLUSIONS These observations are suggestive of two distinct developmental pathways leading to the acceleration of pubertal timing but with different consequences for ovarian function. We suggest different adaptive explanations for these pathways and for their relationship to altered metabolic homeostasis.
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Salles JP, Gennero I, Moulin P, Conte-Auriol F, Edouard T, Tauber M. Facteurs de l’ostéogenèse chez l’enfant. Arch Pediatr 2009; 16:611-3. [DOI: 10.1016/s0929-693x(09)74086-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Abstract
Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this article, we discuss three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator-activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.
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Torday JS, Rehan VK. Cell-cell signaling drives the evolution of complex traits: introduction-lung evo-devo. Integr Comp Biol 2009; 49:142-54. [PMID: 20607136 PMCID: PMC2895351 DOI: 10.1093/icb/icp017] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Physiology integrates biology with the environment through cell–cell interactions at multiple levels. The evolution of the respiratory system has been “deconvoluted” (Torday and Rehan in Am J Respir Cell Mol Biol 31:8–12, 2004) through Gene Regulatory Networks (GRNs) applied to cell–cell communication for all aspects of lung biology development, homeostasis, regeneration, and aging. Using this approach, we have predicted the phenotypic consequences of failed signaling for lung development, homeostasis, and regeneration based on evolutionary principles. This cell–cell communication model predicts other aspects of vertebrate physiology as adaptational responses. For example, the oxygen-induced differentiation of alveolar myocytes into alveolar adipocytes was critical for the evolution of the lung in land dwelling animals adapting to fluctuating Phanarezoic oxygen levels over the past 500 million years. Adipocytes prevent lung injury due to oxygen radicals and facilitate the rise of endothermy. In addition, they produce the class I cytokine leptin, which augments pulmonary surfactant activity and alveolar surface area, increasing selection pressure for both respiratory oxygenation and metabolic demand initially constrained by high-systemic vascular pressure, but subsequently compensated by the evolution of the adrenomedullary beta-adrenergic receptor mechanism. Conserted positive selection for the lung and adrenals created further selection pressure for the heart, which becomes progressively more complex phylogenetically in tandem with the lung. Developmentally, increasing heart complexity and size impinges precociously on the gut mesoderm to induce the liver. That evolutionary-developmental interaction is significant because the liver provides regulated sources of glucose and glycogen to the evolving physiologic system, which is necessary for the evolution of the neocortex. Evolution of neocortical control furthers integration of physiologic systems. Such an evolutionary vertical integration of cell-to-tissue-to-organ-to-physiology of intrinsic cell–cell signaling and extrinsic factors is the reverse of the “top-down” conventional way in which physiologic systems are usually regarded. This novel mechanistic approach, incorporating a “middle-out” cell–cell signaling component, will lead to a readily available algorithm for integrating genes and phenotypes. This symposium surveyed the phylogenetic origins of such vertically integrated mechanisms for the evolution of cell–cell communication as the basis for complex physiologic traits, from sponges to man.
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Affiliation(s)
- John S Torday
- Laboratory for Evolutionary Preventive Medicine, Department of Pediatrics, David Geffen School of Medicine at UCLA, Laboratory for Evolutionary Preventive Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
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Motyl KJ, McCabe LR. Leptin treatment prevents type I diabetic marrow adiposity but not bone loss in mice. J Cell Physiol 2008; 218:376-84. [PMID: 18932203 DOI: 10.1002/jcp.21608] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Leptin is a hormone secreted by adipocytes that is implicated in the regulation of bone density. Serum leptin levels are decreased in rodent models of type 1 (T1-) diabetes and in diabetic patients. Whether leptin mediates diabetic bone changes is unclear. Therefore, we treated control and T1-diabetic mice with chronic (28 days) subcutaneous infusion of leptin or saline to elucidate the therapeutic potential of leptin for diabetic osteoporosis. Leptin prevented the increase of marrow adipocytes and the increased aP2 expression that we observed in vehicle-treated diabetic mice. However, leptin did not prevent T1-diabetic decreases in trabecular bone volume fraction or bone mineral density in tibia or vertebrae. Consistent with this finding, markers of bone formation (osteocalcin RNA and serum levels) in diabetic mice were not restored to normal levels with leptin treatment. Interestingly, markers of bone resorption (TRAP5 RNA and serum levels) were decreased in diabetic mice by leptin treatment. In summary, we have demonstrated a link between low leptin levels in T1-diabetes and marrow adiposity. However, leptin treatment alone was not successful in preventing bone loss.
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Affiliation(s)
- Katherine J Motyl
- Department of Physiology, Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan, USA
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