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Smith C, Lin X, Parker L, Yeap BB, Hayes A, Levinger I. The role of bone in energy metabolism: A focus on osteocalcin. Bone 2024; 188:117238. [PMID: 39153587 DOI: 10.1016/j.bone.2024.117238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant. Recently, bone was recognized as an endocrine organ, with several bone proteins, known as osteokines, implicated in glucose metabolism through their effects on the liver, skeletal muscle, and adipose tissue. Research efforts mostly focused on osteocalcin (OC) as a leading example. This review will provide an overview on this role of bone by discussing bone turnover markers (BTMs), the receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), sclerostin (SCL) and lipocalin 2 (LCN2), with a focus on OC. Since 2007, some, but not all, research using mostly OC genetically modified animal models suggested undercarboxylated (uc) OC acts as a hormone involved in energy metabolism. Most data generated from in vivo, ex vivo and in vitro models, indicate that exogenous ucOC administration improves whole-body and skeletal muscle glucose metabolism. Although data in humans are generally supportive, findings are often discordant likely due to methodological differences and observational nature of that research. Overall, evidence supports the concept that bone-derived factors are involved in energy metabolism, some having beneficial effects (ucOC, OPG) others negative (RANKL, SCL), with the role of some (LCN2, other BTMs) remaining unclear. Whether the effect of osteokines on glucose regulation is clinically significant and of therapeutic value for people with insulin resistance and T2D remains to be confirmed.
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Affiliation(s)
- Cassandra Smith
- Nutrition & Health Innovation Research Institute, School of Health and Medical Sciences, Edith Cowan University, Perth, Western Australia, Australia; Medical School, The University of Western Australia, Perth, Western Australia, Australia; Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia
| | - Xuzhu Lin
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Lewan Parker
- Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC, Australia
| | - Bu B Yeap
- Medical School, The University of Western Australia, Perth, Western Australia, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
| | - Alan Hayes
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia.
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Nahm CH, Lee MH, Fujii N, Fujii T, Choi JW. The Role of Nitric Oxide, Lipocalin-2, and Proinflammatory Cytokines on Proteinuria and Insulin Resistance in Type 2 Diabetes Mellitus Subgroups. Int J Gen Med 2024; 17:4973-4984. [PMID: 39494356 PMCID: PMC11531234 DOI: 10.2147/ijgm.s478584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
Background Nitric oxide (NO) is a bioactive signaling molecule that mediates various physiological and biological processes. Type 2 diabetes mellitus (T2DM) can be categorized into several subgroups according to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. Few studies have closely examined the effect of NO and lipocalin-2 on albuminuria and insulin resistance in T2DM subgroups. This study investigated the role of NO, lipocalin-2, and proinflammatory cytokines on the development of proteinuria and insulin resistance in patients with T2DM subgroups. Methods A total of 256 subjects, including 191 patients with T2DM and 65 non-diabetic healthy individuals, were evaluated. NO metabolites (NOx), lipocalin-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured. Patients with T2DM were classified into three subgroups: patients with FPG-defined diabetes (PG-DM), those with HbA1c-defined diabetes (HA-DM), and those who met the criteria for both FPG and HbA1c (PG/HA-DM). The albumin-to-creatinine ratio (ACR) and the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated. Results NOx, lipocalin-2, and TNF-α levels were significantly higher in patients with T2DM than in healthy individuals. Patients with PG/HA-DM had significantly higher NOx levels than those with PG-DM or HA-DM. Of the patients with high NOx levels, patients with lipocalin-2 elevation exhibited higher ACR and HOMA-IR than those without lipocalin-2 elevation. NOx was positively correlated with lipocalin-2, ACR, HOMA-IR, and TNF-α but not with HOMA-B and IL-6. The upper quartile of NOx levels led to a 1.2-fold increase in the risk of albuminuria (odds ratio: 1.215; 95% CI: 1.012-2.418; p < 0.001). Conclusion NO plays a crucial role in proteinuria and insulin resistance by collaborating with lipocalin-2 and TNF-α, showing significantly higher levels in patients with PG/HA-DM than in those with PG-DM or HA-DM.
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Affiliation(s)
- Chung Hyun Nahm
- Department of Laboratory Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Moon Hee Lee
- Department of Internal Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Noriyoshi Fujii
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Tatsuyoshi Fujii
- Department of Internal Medicine, Teikyo University Chiba Medical Center, Chiba, Japan
| | - Jong Weon Choi
- Department of Laboratory Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
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Zhang W, Chen S, Zhuang X. Research Progress on Lipocalin-2 in Diabetic Encephalopathy. Neuroscience 2023; 515:74-82. [PMID: 36805002 DOI: 10.1016/j.neuroscience.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/07/2023] [Accepted: 02/12/2023] [Indexed: 02/18/2023]
Abstract
Diabetic encephalopathy is a central nervous complication of diabetes mellitus which is characterized by cognitive impairment and structural and neurochemical abnormalities, which is easily neglected. Lipocalin-2 (LCN2) is a 25 kDa transporter in the lipocalin family that can transport small molecules, including fatty acids, iron, steroids, and lipopolysaccharides in the circulation. Recently, LCN2 has been found to be a significant regulator of insulin resistance and glucose homeostasis. Numerous studies have shown that LCN2 is connected to central nervous system abnormalities, including neuroinflammation and neurodegeneration, while the latest researches have found that LCN2 is closely related to the development of diabetic encephalopathy. Nevertheless, its precise role in the pathogenesis of diabetic encephalopathy remains to be determined. In this paper, we review recent evidence on the role of LCN2 in diabetic encephalopathy from multiple perspectives in order to decipher the impact of LCN2 in both the aetiology and treatment of diabetic encephalopathy.
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Affiliation(s)
- Wenjie Zhang
- Cheeloo College of Medicine, Shangdong University, Jinan 250000, China
| | - Shihong Chen
- Department of Endocrinology, The Second Hospital of Shandong University, Jinan 250000, China.
| | - Xianghua Zhuang
- Department of Endocrinology, The Second Hospital of Shandong University, Jinan 250000, China.
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Parker L, Ang T, Morrison DJ, Lee NJ, Levinger I, Keske MA. Prior aerobic exercise mitigates the decrease in serum osteoglycin and lipocalin-2 following high-glucose mixed-nutrient meal ingestion in young men. Am J Physiol Endocrinol Metab 2022; 323:E319-E332. [PMID: 35767699 DOI: 10.1152/ajpendo.00025.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Osteoglycin (OGN) and lipocalin-2 (LCN2) are hormones that can be secreted by bone and have been linked to glucose homeostasis in rodents. However, the endocrine role of these hormones in humans is contradictory and unclear. We examined the effects of exercise and meal ingestion on circulating serum OGN and LCN2 levels in eight healthy males {age: 28 [25, 30] years [median ± interquartile range (IQR)] and body mass index [BMI]: 24.3 [23.6, 25.5] kg/m2}. In a randomized crossover design, participants ingested a high-glucose (1.1 g glucose/kg body wt) mixed-nutrient meal (45% carbohydrate, 20% protein, and 35% fat) on a rest-control day and 3 and 24 h after aerobic cycling exercise (1 h at 70%-75% V̇o2peak). Acute aerobic exercise increased serum LCN2 levels immediately after exercise (∼61%), which remained elevated 3-h postexercise (∼55%). In contrast, serum OGN remained similar to baseline levels throughout the 3-h postexercise recovery period. The ingestion of a high-glucose mixed-nutrient meal led to a decrease in serum OGN at 90-min (approximately -17%) and 120-min postprandial (approximately -44%), and a decrease in LCN2 at 120-min postprandial (approximately -26%). Compared with the control meal, prior exercise elevated serum OGN and LCN2 levels at 120-min postprandial when the meal was ingested 3-h (OGN: ∼74% and LCN2: ∼68%) and 24-h postexercise (OGN: ∼56% and LCN2: ∼16%). Acute exercise increases serum LCN2 and attenuates the postprandial decrease in OGN and LCN2 following high-glucose mixed-nutrient meal ingestion. The potential endocrine role of circulating OGN and LCN2 in humans warrants further investigation.NEW & NOTEWORTHY We provide novel evidence that OGN and LCN2 decrease 120 min after ingesting a high-glucose mixed-nutrient meal in healthy adults. Acute aerobic exercise increases circulating LCN2 for up to 3-h postexercise, whereas circulating OGN remains similar to baseline. Despite differing postexercise responses, postprandial LCN2 and OGN are elevated when the high-glucose meal is ingested 3-h and 24-h postexercise. Findings support that OGN and LCN2 are dynamically linked to energy homeostasis in humans.
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Affiliation(s)
- Lewan Parker
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Teddy Ang
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Dale J Morrison
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Nicola J Lee
- Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia
- St. Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Footscray, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St Albans, Victoria, Australia
| | - Michelle A Keske
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
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Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue. Cancers (Basel) 2022; 14:cancers14071679. [PMID: 35406450 PMCID: PMC8996963 DOI: 10.3390/cancers14071679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. Abstract The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
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Daoud MS, Hussain SD, Al-Daghri NM. Cardiometabolic associations of circulating Lipocalin-2 in adults with varying degrees of adiposity and insulin resistance. Arch Biochem Biophys 2022; 717:109138. [DOI: 10.1016/j.abb.2022.109138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 11/02/2022]
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Takashi Y, Kawanami D. The Role of Bone-Derived Hormones in Glucose Metabolism, Diabetic Kidney Disease, and Cardiovascular Disorders. Int J Mol Sci 2022; 23:ijms23042376. [PMID: 35216490 PMCID: PMC8879859 DOI: 10.3390/ijms23042376] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/16/2022] [Accepted: 02/19/2022] [Indexed: 12/19/2022] Open
Abstract
Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works as an endocrine organ and secretes several systemic humoral factors, including fibroblast growth factor 23 (FGF23), osteocalcin (OC), sclerostin, and lipocalin 2. Bone can communicate with other organs via these hormones. In particular, it has been reported that these bone-derived hormones are involved in glucose metabolism and diabetic complications. Some functions of these bone-derived hormones can become useful biomarkers that predict the incidence of diabetes and the progression of diabetic complications. Furthermore, other functions are considered to be targets for the prevention or treatment of diabetes and its complications. As is well known, diabetes is now a worldwide health problem, and many efforts have been made to treat diabetes. Thus, further investigations of the endocrine system through bone-derived hormones may provide us with new perspectives on the prediction, prevention, and treatment of diabetes. In this review, we summarize the role of bone-derived hormones in glucose metabolism, diabetic kidney disease, and cardiovascular disorders.
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Verdú E, Homs J, Boadas-Vaello P. Physiological Changes and Pathological Pain Associated with Sedentary Lifestyle-Induced Body Systems Fat Accumulation and Their Modulation by Physical Exercise. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:13333. [PMID: 34948944 PMCID: PMC8705491 DOI: 10.3390/ijerph182413333] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/02/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022]
Abstract
A sedentary lifestyle is associated with overweight/obesity, which involves excessive fat body accumulation, triggering structural and functional changes in tissues, organs, and body systems. Research shows that this fat accumulation is responsible for several comorbidities, including cardiovascular, gastrointestinal, and metabolic dysfunctions, as well as pathological pain behaviors. These health concerns are related to the crosstalk between adipose tissue and body systems, leading to pathophysiological changes to the latter. To deal with these health issues, it has been suggested that physical exercise may reverse part of these obesity-related pathologies by modulating the cross talk between the adipose tissue and body systems. In this context, this review was carried out to provide knowledge about (i) the structural and functional changes in tissues, organs, and body systems from accumulation of fat in obesity, emphasizing the crosstalk between fat and body tissues; (ii) the crosstalk between fat and body tissues triggering pain; and (iii) the effects of physical exercise on body tissues and organs in obese and non-obese subjects, and their impact on pathological pain. This information may help one to better understand this crosstalk and the factors involved, and it could be useful in designing more specific training interventions (according to the nature of the comorbidity).
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Affiliation(s)
- Enrique Verdú
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain;
| | - Judit Homs
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain;
- Department of Physical Therapy, EUSES-University of Girona, 17190 Salt, Spain
| | - Pere Boadas-Vaello
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain;
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Jeong EA, Lee J, Shin HJ, Lee JY, Kim KE, An HS, Kim DR, Choi KY, Lee KH, Roh GS. Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2. J Neuroinflammation 2021; 18:278. [PMID: 34844610 PMCID: PMC8628424 DOI: 10.1186/s12974-021-02331-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/24/2021] [Indexed: 11/10/2022] Open
Abstract
Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. Methods We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells. Results Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. Conclusions These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02331-8.
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Affiliation(s)
- Eun Ae Jeong
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jaewoong Lee
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jong Youl Lee
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Hyeong Seok An
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Deok Ryong Kim
- Department of Biochemistry, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Kyu Yeong Choi
- Gwangju Alzheimer's Disease and Related Dementia Cohort Research Center, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kun Ho Lee
- Gwangju Alzheimer's Disease and Related Dementia Cohort Research Center, Chosun University, Gwangju, 61452, Republic of Korea. .,Department of Biomedical Science, Chosun University, Gwangju, 61452, Republic of Korea. .,Aging Neuroscience Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea.
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Dekens DW, Eisel ULM, Gouweleeuw L, Schoemaker RG, De Deyn PP, Naudé PJW. Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases. Ageing Res Rev 2021; 70:101414. [PMID: 34325073 DOI: 10.1016/j.arr.2021.101414] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.
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Affiliation(s)
- Doortje W Dekens
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Ulrich L M Eisel
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Leonie Gouweleeuw
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Regien G Schoemaker
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Peter P De Deyn
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Laboratory of Neurochemistry and Behaviour, Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Petrus J W Naudé
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands; Department of Psychiatry and Mental Health and Neuroscience Institute, Brain Behaviour Unit, University of Cape Town, Cape Town, South Africa.
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Sun WX, Lou K, Chen LJ, Liu SD, Pang SG. Lipocalin-2: a role in hepatic gluconeogenesis via AMP-activated protein kinase (AMPK). J Endocrinol Invest 2021; 44:1753-1765. [PMID: 33423221 DOI: 10.1007/s40618-020-01494-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/23/2020] [Indexed: 01/19/2023]
Abstract
PURPOSE Evidence is accumulating that lipocalin2 (LCN2) is implicated in insulin resistance and glucose homeostasis, but the underlying possible mechanisms remain unclear. This study is to investigate the possible linkage between LCN2 and AMP-activated protein kinase (AMPK) or forkhead transcription factor O1 (FoxO1), which influences insulin sensitivity and gluconeogenesis in liver. METHODS LCN2 knockout (LCN2KO) mice and wild-type littermates were used to evaluate the effect of LCN2 on insulin sensitivity and hepatic gluconeogenesis through pyruvate tolerance test (PTT), glucose tolerance test (ipGTT), insulin tolerance test (ITT), and hyperinsulinemic-euglycemic clamps, respectively. LCN2KO mice and WT mice in vivo, and in vitro HepG2 cells were co-transfected with adenoviral FoxO1-siRNA (Ad-FoxO1-siRNA) or adenovirus expressing constitutively active form of AMPK (Ad-CA-AMPK), or dominant negative adenovirus AMPK (Ad-DN-AMPK), the relative mRNA and protein levels of two key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P) were measured. RESULTS Improved insulin sensitivity and inhibited gluconeogenesis in the LCN2KO mice were confirmed by pyruvate tolerance tests and hyperinsulinemic-euglycemic clamps. Nuclear FoxO1 and its downstream genes PEECK and G6P were decreased in the livers of the LCN2KO mice, and AMPK activity was stimulated and directly phosphorylated FoxO1. In vitro, AMPK activity was inhibited in HepG2 cells overexpressing LCN2 leading to a decrease in phosphorylated FoxO1 and an increase in nuclear FoxO1. CONCLUSION The present study demonstrates that LCN2 regulates insulin sensitivity and glucose metabolism through inhibiting AMPK activity, and regulating FoxO1 and its downstream genes PEPCK/G6P, which regulate hepatic gluconeogenesis.
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Affiliation(s)
- W-X Sun
- Department of Pharmacy, Taishan Vocational College of Nursing, Taian, 271000, China
| | - K Lou
- Department of Endocrinology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, 105 Jiefang Road, Jinan, 250013, Shandong Province, China
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China
| | - L-J Chen
- Department of Endocrinology, Shandong Rongjun General Hospital, 23 Jiefang Road, Jinan, 250013, Shandong Province, China
| | - S-D Liu
- Department of Endocrinology, Shandong Rongjun General Hospital, 23 Jiefang Road, Jinan, 250013, Shandong Province, China.
| | - S-G Pang
- Department of Endocrinology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, 105 Jiefang Road, Jinan, 250013, Shandong Province, China.
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China.
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12
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Skeletal Lipocalin-2 Is Associated with Iron-Related Oxidative Stress in ob/ob Mice with Sarcopenia. Antioxidants (Basel) 2021; 10:antiox10050758. [PMID: 34064680 PMCID: PMC8150392 DOI: 10.3390/antiox10050758] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/01/2021] [Accepted: 05/10/2021] [Indexed: 12/03/2022] Open
Abstract
Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.
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13
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Olson B, Zhu X, Norgard MA, Levasseur PR, Butler JT, Buenafe A, Burfeind KG, Michaelis KA, Pelz KR, Mendez H, Edwards J, Krasnow SM, Grossberg AJ, Marks DL. Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia. Nat Commun 2021; 12:2057. [PMID: 33824339 PMCID: PMC8024334 DOI: 10.1038/s41467-021-22361-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 03/12/2021] [Indexed: 12/22/2022] Open
Abstract
Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2's proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.
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Affiliation(s)
- Brennan Olson
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
- Medical Scientist Training Program, Oregon Health & Science University, Portland, OR, USA
| | - Xinxia Zhu
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Mason A Norgard
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Peter R Levasseur
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - John T Butler
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
- Medical Scientist Training Program, Oregon Health & Science University, Portland, OR, USA
| | - Abigail Buenafe
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Kevin G Burfeind
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
- Medical Scientist Training Program, Oregon Health & Science University, Portland, OR, USA
| | - Katherine A Michaelis
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
- Medical Scientist Training Program, Oregon Health & Science University, Portland, OR, USA
| | - Katherine R Pelz
- Brenden-Colson Center for Pancreatic Care, Oregon Health and & Science University, Portland, OR, USA
| | - Heike Mendez
- Brenden-Colson Center for Pancreatic Care, Oregon Health and & Science University, Portland, OR, USA
| | - Jared Edwards
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Stephanie M Krasnow
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Aaron J Grossberg
- Brenden-Colson Center for Pancreatic Care, Oregon Health and & Science University, Portland, OR, USA
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR, USA
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Daniel L Marks
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.
- Brenden-Colson Center for Pancreatic Care, Oregon Health and & Science University, Portland, OR, USA.
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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14
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Oxidative Stress and Low-Grade Inflammation in Polycystic Ovary Syndrome: Controversies and New Insights. Int J Mol Sci 2021; 22:ijms22041667. [PMID: 33562271 PMCID: PMC7915804 DOI: 10.3390/ijms22041667] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
The pathophysiology of Polycystic Ovary Syndrome (PCOS) is quite complex and different mechanisms could contribute to hyperandrogenism and anovulation, which are the main features of the syndrome. Obesity and insulin-resistance are claimed as the principal factors contributing to the clinical presentation; in normal weight PCOS either, increased visceral adipose tissue has been described. However, their role is still debated, as debated are the biochemical markers linked to obesity per se. Oxidative stress (OS) and low-grade inflammation (LGI) have recently been a matter of researcher attention; they can influence each other in a reciprocal vicious cycle. In this review, we summarize the main mechanism of radical generation and the link with LGI. Furthermore, we discuss papers in favor or against the role of obesity as the first pathogenetic factor, and show how OS itself, on the contrary, can induce obesity and insulin resistance; in particular, the role of GH-IGF-1 axis is highlighted. Finally, the possible consequences on vitamin D synthesis and activation on the immune system are briefly discussed. This review intends to underline the key role of oxidative stress and low-grade inflammation in the physiopathology of PCOS, they can cause or worsen obesity, insulin-resistance, vitamin D deficiency, and immune dyscrasia, suggesting an inverse interaction to what is usually considered.
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15
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Bhusal A, Lee WH, Suk K. Lipocalin-2 in Diabetic Complications of the Nervous System: Physiology, Pathology, and Beyond. Front Physiol 2021; 12:638112. [PMID: 33613327 PMCID: PMC7892766 DOI: 10.3389/fphys.2021.638112] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 01/19/2021] [Indexed: 01/04/2023] Open
Abstract
Lipocalin-2 (LCN2) is a 25 kDa secreted protein that belongs to the family of lipocalins, a group of transporters of small hydrophobic molecules such as iron, fatty acids, steroids, and lipopolysaccharide in circulation. LCN2 was previously found to be involved in iron delivery, pointing toward a potential role for LCN2 in immunity. This idea was further validated when LCN2 was found to limit bacterial growth during infections in mice by sequestering iron-laden siderophores. Recently, LCN2 was also identified as a critical regulator of energy metabolism, glucose and lipid homeostasis, and insulin function. Furthermore, studies using Lcn2 knockout mice suggest an important role for LCN2 in several biobehavioral responses, including cognition, emotion, anxiety, and feeding behavior. Owing to its expression and influence on multiple metabolic and neurological functions, there has emerged a great deal of interest in the study of relationships between LCN2 and neurometabolic complications. Thorough investigation has demonstrated that LCN2 is involved in several neurodegenerative diseases, while more recent studies have shown that LCN2 is also instrumental for the progression of diabetic complications like encephalopathy and peripheral neuropathy. Preliminary findings have shown that LCN2 is also a promising drug target and diagnostic marker for the treatment of neuropathic complications from diabetes. In particular, future translational research related to LCN2, such as the development of small-molecule inhibitors or neutralizing antibodies against LCN2, appears essential for exploring its potential as a therapeutic target.
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Affiliation(s)
- Anup Bhusal
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Won-Ha Lee
- School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Kyoungho Suk
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, South Korea.,Brain Science and Engineering Institute, Kyungpook National University, Daegu, South Korea
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16
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Bühler L, Maida A, Vogl ES, Georgiadi A, Takacs A, Kluth O, Schürmann A, Feuchtinger A, von Toerne C, Tsokanos FF, Klepac K, Wolff G, Sakurai M, Ekim Üstünel B, Nawroth P, Herzig S. Lipocalin 13 enhances insulin secretion but is dispensable for systemic metabolic control. Life Sci Alliance 2021; 4:4/4/e202000898. [PMID: 33536239 PMCID: PMC7898469 DOI: 10.26508/lsa.202000898] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/12/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Thorough preclinical evaluation reveals a negligible role of lipocalin 13 in systemic glucose and lipid metabolism. Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernible impact on systemic glucose and lipid metabolism, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects.
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Affiliation(s)
- Lea Bühler
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Adriano Maida
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Elena Sophie Vogl
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Anastasia Georgiadi
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andrea Takacs
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Oliver Kluth
- German Center for Diabetes Research (DZD), Neuherberg, Germany.,Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - Annette Schürmann
- German Center for Diabetes Research (DZD), Neuherberg, Germany.,Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.,Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Annette Feuchtinger
- Research Unit Analytical Pathology, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Christine von Toerne
- Research Unit Protein Science, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Foivos-Filippos Tsokanos
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Katarina Klepac
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Gretchen Wolff
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Minako Sakurai
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Bilgen Ekim Üstünel
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Peter Nawroth
- Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Stephan Herzig
- Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany .,Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Munich, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
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17
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Currò D, Vergani E, Bruno C, Comi S, D'Abate C, Mancini A. Plasmatic lipocalin-2 levels in chronic low-grade inflammation syndromes: Comparison between metabolic syndrome, total and partial adult growth hormone deficiency. Biofactors 2020; 46:629-636. [PMID: 32196782 DOI: 10.1002/biof.1628] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/23/2019] [Accepted: 02/29/2020] [Indexed: 12/13/2022]
Abstract
Lipocalin-2 (LCN2) is a secreted glycoprotein involved in several chronic inflammatory processes. Metabolic syndrome (MetS) and adult growth hormone deficiency (GHD) are known as chronic inflammatory conditions. The primary objective of this observational cross-sectional study was to compare LCN2 plasmatic levels in these clinical settings, whereas the secondary objective was to investigate any possible correlation between LCN2 and BMI and/or indexes of insulin sensitivity/resistance. Seventy-four patients were divided as follows: Group A, MetS (18 patients, 13 females and 5 males, mean ± SEM age 45.1 ± 4.11 years, BMI 31.22 ± 1.73 kg/m2 ); Group B, total GHD (18 patients, 8 females and 10 males, age 52.44 ± 2.61 years, BMI 30.49 ± 1.87 kg/m2 ); Group C, Partial GHD (pGHD; 19 patients, 13 females and 6 males, age 48.63 ± 2.19 years, BMI 29.11 ± 1.85 kg/m2 ); Group D, Controls (19 patients, 13 females and 6males, age 40.26 ± 2.87 years, BMI 23.25 ± 0.95 kg/m2 ). They were evaluated for glucose and insulin, HOMA-index, QUICKI-index, Total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides, uric acid, IGF-1, and LCN2. LCN2 plasmatic levels were significantly increased in MetS, while no significant differences with controls were found in total and pGHD. LCN2 levels did not correlate with BMI. A significant positive correlation between LCN2 and HOMA-index was found in controls, while a trend-like, yet not significant, a positive correlation was observed in pGHD. Our data show an increase in LCN2 plasmatic levels in MetS. Different inflammatory patterns characterize MetS and GHD. The correlation between HOMA index and LCN2 in normal subjects and possibly in pGHD ones suggests a modulatory action of LCN2 on insulin resistance.
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Affiliation(s)
- Diego Currò
- Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Roma, Italy
- Unità Operativa Complessa di Farmacologia, Direzione Sanitaria, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - Edoardo Vergani
- UOC Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Carmine Bruno
- UOC Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Simone Comi
- UOC Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Claudia D'Abate
- UOC Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Antonio Mancini
- UOC Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
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18
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Lin X, Onda DA, Yang CH, Lewis JR, Levinger I, Loh K. Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology. Mol Metab 2020; 40:101040. [PMID: 32544571 PMCID: PMC7348059 DOI: 10.1016/j.molmet.2020.101040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/28/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones—osteocalcin, lipocalin 2, and sclerostin—are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation is one of the hallmarks of cardiometabolic diseases and a major contributor to disease progression. Novel evidence also implicates important roles of bone-derived hormones in the regulation of chronic inflammation. Scope of review In this review, we provide a detailed overview of the physiological and pathological roles of osteocalcin, lipocalin 2, and sclerostin in cardiometabolic health regulation and disease development, with a focus on the modulation of chronic inflammation. Major conclusions Evidence supports that osteocalcin has a protective role in cardiometabolic health, and an increase of lipocalin 2 contributes to the development of cardiometabolic diseases partly via pro-inflammatory effects. The roles of sclerostin appear to be complicated: It exerts pro-adiposity and pro-insulin resistance effects in type 2 diabetes and has an anti-calcification effect during cardiovascular disease. A better understanding of the actions of these bone-derived hormones in the pathophysiology of cardiometabolic diseases will provide crucial insights to help further research develop new therapeutic strategies to treat these diseases.
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Affiliation(s)
- Xuzhu Lin
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
| | - Danise-Ann Onda
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Chieh-Hsin Yang
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Joshua R Lewis
- School of Medical and Health Sciences, Edith Cowan University, Perth, Australia; Medical School, University of Western Australia, Perth, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Footscray, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St Albans, VIC, Australia
| | - Kim Loh
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
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19
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Abstract
Osteoblasts are specialized mesenchymal cells that synthesize bone matrix and coordinate the mineralization of the skeleton. These cells work in harmony with osteoclasts, which resorb bone, in a continuous cycle that occurs throughout life. The unique function of osteoblasts requires substantial amounts of energy production, particularly during states of new bone formation and remodelling. Over the last 15 years, studies have shown that osteoblasts secrete endocrine factors that integrate the metabolic requirements of bone formation with global energy balance through the regulation of insulin production, feeding behaviour and adipose tissue metabolism. In this article, we summarize the current understanding of three osteoblast-derived metabolic hormones (osteocalcin, lipocalin and sclerostin) and the clinical evidence that suggests the relevance of these pathways in humans, while also discussing the necessity of specific energy substrates (glucose, fatty acids and amino acids) to fuel bone formation and promote osteoblast differentiation.
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Affiliation(s)
- Naomi Dirckx
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Megan C Moorer
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
| | - Thomas L Clemens
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
| | - Ryan C Riddle
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- The Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
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20
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Funcke JB, Scherer PE. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res 2019; 60:1648-1684. [PMID: 31209153 PMCID: PMC6795086 DOI: 10.1194/jlr.r094060] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/17/2019] [Indexed: 01/10/2023] Open
Abstract
The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs. We discuss recently identified adipokines (proteins, lipids, and metabolites) and briefly outline the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissue inter-organ communication. We conclude by reflecting on central aspects of adipokine biology, namely, the contribution of distinct adipose tissue depots and cell types to adipokine secretion, the phenomenon of adipokine resistance, and the capacity of adipose tissue to act both as a source and sink of signaling mediators.
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Affiliation(s)
- Jan-Bernd Funcke
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Philipp E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
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21
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Chella Krishnan K, Sabir S, Shum M, Meng Y, Acín-Pérez R, Lang JM, Floyd RR, Vergnes L, Seldin MM, Fuqua BK, Jayasekera DW, Nand SK, Anum DC, Pan C, Stiles L, Péterfy M, Reue K, Liesa M, Lusis AJ. Sex-specific metabolic functions of adipose Lipocalin-2. Mol Metab 2019; 30:30-47. [PMID: 31767179 PMCID: PMC6812340 DOI: 10.1016/j.molmet.2019.09.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/04/2019] [Accepted: 09/22/2019] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and has also been associated with several cardiometabolic traits in both mouse and human studies. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males. METHODS Using adeno-associated viral vectors we expressed LCN2 in either adipose or liver in a tissue specific manner on the background of a whole-body Lcn2 knockout or wildtype mice. Metabolic phenotypes including body weight, body composition, plasma and liver lipids, glucose homeostasis, insulin resistance, mitochondrial phenotyping, and metabolic cage studies were monitored. RESULTS We studied the genetics of LCN2 expression and associated clinical traits in both males and females in a panel of 100 inbred strains of mice (HMDP). The natural variation in Lcn2 expression across the HMDP exhibits high heritability, and genetic mapping suggests that it is regulated in part by Lipin1 gene variation. The correlation analyses revealed striking tissue dependent sex differences in obesity, insulin resistance, hepatic steatosis, and dyslipidemia. To understand the causal relationships, we examined the effects of expression of LCN2 selectively in liver or adipose. On a Lcn2-null background, LCN2 expression in white adipose promoted metabolic disturbances in females but not males. It acted in an autocrine/paracrine manner, resulting in mitochondrial dysfunction and an upregulation of inflammatory and fibrotic genes. On the other hand, on a null background, expression of LCN2 in liver had no discernible impact on the traits examined despite increasing the levels of circulating LCN2 more than adipose LCN2 expression. The mechanisms underlying the sex-specific action of LCN2 are unclear, but our results indicate that adipose LCN2 negatively regulates its receptor, LRP2 (or megalin), and its repressor, ERα, in a female-specific manner and that the effects of LCN2 on metabolic traits are mediated in part by LRP2. CONCLUSIONS Following up on our population-based studies, we demonstrate that LCN2 acts in a highly sex- and tissue-specific manner in mice. Our results have important implications for human studies, emphasizing the importance of sex and the tissue source of LCN2.
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Affiliation(s)
| | - Simon Sabir
- Department of Psychology, University of California, Los Angeles, CA, USA
| | - Michaël Shum
- Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA
| | - Yonghong Meng
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
| | - Rebeca Acín-Pérez
- Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA
| | - Jennifer M Lang
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
| | - Raquel R Floyd
- Department of Biology, University of California, Los Angeles, CA, USA
| | - Laurent Vergnes
- Department of Human Genetics, University of California, Los Angeles, CA, USA
| | - Marcus M Seldin
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
| | - Brie K Fuqua
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
| | - Dulshan W Jayasekera
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA
| | - Sereena K Nand
- Department of Biology, University of California, Los Angeles, CA, USA
| | - Diana C Anum
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Calvin Pan
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
| | - Linsey Stiles
- Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA
| | - Miklós Péterfy
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA; Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA, USA
| | - Karen Reue
- Department of Human Genetics, University of California, Los Angeles, CA, USA
| | - Marc Liesa
- Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Aldons J Lusis
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.
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22
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Bhusal A, Rahman MH, Lee WH, Bae YC, Lee IK, Suk K. Paradoxical role of lipocalin-2 in metabolic disorders and neurological complications. Biochem Pharmacol 2019; 169:113626. [PMID: 31476294 DOI: 10.1016/j.bcp.2019.113626] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023]
Abstract
Lipocalin-2 (LCN2), also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), is a 25-kDa secreted protein implicated in various metabolic and inflammatory diseases. Early studies suggest the protective function of LCN2 in which it acts as a bacteriostatic agent that competes with bacteria for iron-bound siderophores. However, both detrimental and beneficial roles of LCN2 have recently been documented in metabolic and neuroinflammatory diseases. Metabolic inflammation, as observed in diabetes and obesity, has been closely associated with the upregulation of LCN2 in blood plasma and several tissues in both humans and rodents, suggesting its pro-diabetic and pro-obesogenic role. On the contrary, other studies imply an anti-diabetic and anti-obesogenic role of LCN2 whereby a deficiency in the Lcn2 gene results in the impairment of insulin sensitivity and enhances the high-fat-diet-induced expansion of fat. A similar dual role of LCN2 has also been reported in various animal models for neurological disorders. In the midst of these mixed findings, there is no experimental evidence to explain why LCN2 shows such a contrasting role in the various studies. This debate needs to be resolved (or reconciled) and an integrated view on the topic is desirable. Herein, we attempt to address this issue by reviewing the recent findings on LCN2 in metabolic disorders and assess the potential cellular or molecular mechanisms underlying the dual role of LCN2. We further discuss the possibilities and challenges of targeting LCN2 as a potential therapeutic strategy for metabolic disorders and neurological complications.
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Affiliation(s)
- Anup Bhusal
- Department of Pharmacology, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Biomedical Science, BK21 PLUS KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Md Habibur Rahman
- Department of Pharmacology, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Biomedical Science, BK21 PLUS KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Won-Ha Lee
- School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea
| | - Yong Chul Bae
- Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, Division of Endocrinology and Metabolism, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Kyoungho Suk
- Department of Pharmacology, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Biomedical Science, BK21 PLUS KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
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23
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Deis JA, Guo H, Wu Y, Liu C, Bernlohr DA, Chen X. Adipose Lipocalin 2 overexpression protects against age-related decline in thermogenic function of adipose tissue and metabolic deterioration. Mol Metab 2019; 24:18-29. [PMID: 30928474 PMCID: PMC6531839 DOI: 10.1016/j.molmet.2019.03.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 11/01/2022] Open
Abstract
OBJECTIVES Aging increases the risk for development of adipose tissue dysfunction, insulin resistance, dyslipidemia, and liver steatosis. Lipocalin 2 (Lcn2) deficient mice are more prone to diet-induced obesity and metabolic dysfunction, indicating a protective role for Lcn2 in younger mice. In this study, we determined whether overexpressing Lcn2 in adipose tissue can protect against age-related metabolic deterioration. METHODS We developed ap2-promoter-driven Lcn2 transgenic (Tg) mice and aged Lcn2 Tg mice for the metabolic assessments. RESULTS We found decreased adipocyte size in inguinal white adipose tissue (iWAT) from 10-month-old Lcn2 Tg mice relative to WT. This was accompanied by increased markers of adipogenesis in iWAT and attenuation of the age-related decline in AMP-activated protein kinase (AMPK) phosphorylation in adipose tissue depots. In addition to improvements in adipose tissue function, whole-body metabolic homeostasis was maintained in aged Lcn2 Tg mice. This included improved glucose tolerance and reduced serum triglycerides in older Lcn2 Tg mice relative to WT mice. Further, liver morphology and liver lipid levels were improved in older Lcn2 Tg mice, alongside a decrease in markers of liver inflammation and fibrosis. CONCLUSIONS We demonstrate that overexpression of Lcn2 in adipose tissue not only preserves adipose tissue function during aging but also promotes maintenance of glucose tolerance, decreases dyslipidemia, and prevents liver lipid accumulation and steatosis.
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Affiliation(s)
- Jessica A Deis
- Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN, USA
| | - Hong Guo
- Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN, USA
| | - Yingjie Wu
- Institute for Genomic Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China
| | - Chengyu Liu
- Transgenic Core, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, MD, USA
| | - David A Bernlohr
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Twin Cities, MN, USA
| | - Xiaoli Chen
- Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN, USA.
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Abstract
Glucocorticoids are steroid hormones that play a key role in metabolic adaptations during stress, such as fasting and starvation, in order to maintain plasma glucose levels. Excess and chronic glucocorticoid exposure, however, causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. Studies in animal models of metabolic disorders frequently demonstrate that suppressing glucocorticoid signaling improves insulin sensitivity and metabolic profiles. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator. The adipocyte is one cell type that contributes to whole body metabolic homeostasis under the influence of GR. Glucocorticoids' functions on adipose tissues are complex. Depending on various physiological or pathophysiological states as well as distinct fat depots, glucocorticoids can either increase or decrease lipid storage in adipose tissues. In rodents, glucocorticoids have been shown to reduce the thermogenic activity of brown adipocytes. However, in human acute glucocorticoid exposure, glucocorticoids act to promote thermogenesis. In this article, we will review the recent studies on the mechanisms underlying the complex metabolic functions of GR in adipocytes. These include studies of the metabolic outcomes of adipocyte specific GR knockout mice and identification of novel GR primary target genes that mediate glucocorticoid action in adipocytes.
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Affiliation(s)
- Rebecca A Lee
- Endocrinology Graduate Program and Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, CA 94720-3104, USA
| | - Charles A Harris
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Jen-Chywan Wang
- Endocrinology Graduate Program and Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, CA 94720-3104, USA
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Liu DM, Mosialou I, Liu JM. Bone: Another potential target to treat, prevent and predict diabetes. Diabetes Obes Metab 2018; 20:1817-1828. [PMID: 29687585 DOI: 10.1111/dom.13330] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/16/2018] [Accepted: 04/18/2018] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.
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Affiliation(s)
- Dong-Mei Liu
- Department of Rheumatology, ZhongShan Hospital, FuDan University, Shanghai, China
| | - Ioanna Mosialou
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Jian-Min Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai, China
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26
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Mera P, Ferron M, Mosialou I. Regulation of Energy Metabolism by Bone-Derived Hormones. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a031666. [PMID: 28778968 DOI: 10.1101/cshperspect.a031666] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Like many other organs, bone can act as an endocrine organ through the secretion of bone-specific hormones or "osteokines." At least two osteokines are implicated in the control of glucose and energy metabolism: osteocalcin (OCN) and lipocalin-2 (LCN2). OCN stimulates the production and secretion of insulin by the pancreatic β-cells, but also favors adaptation to exercise by stimulating glucose and fatty acid (FA) utilization by the muscle. Both of these OCN functions are mediated by the G-protein-coupled receptor GPRC6A. In contrast, LCN2 influences energy metabolism by activating appetite-suppressing signaling in the brain. This action of LCN2 occurs through its binding to the melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVN) and ventromedial neurons of the hypothalamus.
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Affiliation(s)
- Paula Mera
- Columbia University Medical Center, New York, New York 10032
| | - Mathieu Ferron
- Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada
| | - Ioanna Mosialou
- Columbia University Medical Center, New York, New York 10032
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27
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Obesity-promoting and anti-thermogenic effects of neutrophil gelatinase-associated lipocalin in mice. Sci Rep 2017; 7:15501. [PMID: 29138470 PMCID: PMC5686189 DOI: 10.1038/s41598-017-15825-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 11/01/2017] [Indexed: 01/22/2023] Open
Abstract
Neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2 or LCN2) is an iron carrier protein whose circulating level is increased by kidney injury, bacterial infection and obesity, but its metabolic consequence remains elusive. To study physiological role of LCN2 in energy homeostasis, we challenged female Lcn2 knockout (KO) and wild-type (WT) mice with high fat diet (HFD) or cold exposure. Under normal diet, physical constitutions of Lcn2 KO and WT mice were indistinguishable. During HFD treatment, Lcn2 KO mice exhibited larger brown adipose tissues (BAT), consumed more oxygen, ate more food and gained less body weights as compared to WT mice. When exposed to 4 °C, KO mice showed higher body temperature and more intense 18F-fluorodeoxyglucose uptake in BAT, which were cancelled by β3 adrenergic receptor blocker or iron-loaded (but not iron-free) LCN2 administration. These findings suggest that circulating LCN2 possesses obesity-promoting and anti-thermogenic effects through inhibition of BAT activity in an iron-dependent manner.
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28
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Abstract
Lipocalin 2 (Lcn2), an innate immune protein, has emerged as a critical iron regulatory protein during physiological and inflammatory conditions. As a bacteriostatic factor, Lcn2 obstructs the siderophore iron-acquiring strategy of bacteria and thus inhibits bacterial growth. As part of host nutritional immunity, Lcn2 facilitates systemic, cellular, and mucosal hypoferremia during inflammation, in addition to stabilizing the siderophore-bound labile iron pool. In this review, we summarize recent advances in understanding the interaction between Lcn2 and iron, and its effects in various inflammatory diseases. Lcn2 exerts mostly a protective role in infectious and inflammatory bowel diseases, whereas both beneficial and detrimental functions have been documented in neurodegenerative diseases, metabolic syndrome, renal disorders, skin disorders, and cancer. Further animal and clinical studies are necessary to unveil the multifaceted roles of Lcn2 in iron dysregulation during inflammation and to explore its therapeutic potential for treating inflammatory diseases.
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Affiliation(s)
- Xia Xiao
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802;
| | - Beng San Yeoh
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802;
| | - Matam Vijay-Kumar
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802; .,Department of Medicine, The Pennsylvania State University Medical Center, Hershey, Pennsylvania 17033
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29
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Moschen AR, Adolph TE, Gerner RR, Wieser V, Tilg H. Lipocalin-2: A Master Mediator of Intestinal and Metabolic Inflammation. Trends Endocrinol Metab 2017; 28:388-397. [PMID: 28214071 DOI: 10.1016/j.tem.2017.01.003] [Citation(s) in RCA: 256] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 02/07/2023]
Abstract
Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of inflammation, ischemia, infection, and kidney damage. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased LCN2 synthesis. While LCN2 in the intestinal tract regulates the composition of the gut microbiota and shows anti-inflammatory activities, it also exhibits proinflammatory activities in other experimental settings. In animal models of metabolic inflammation, type 2 diabetes mellitus (T2DM), or nonalcoholic steatohepatitis (NASH), increased LCN2 expression favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines. A better understanding of this crucial marker of innate immunity might pave the way for targeting this pathway in future therapies.
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Affiliation(s)
- Alexander R Moschen
- Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology and Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology and Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria
| | - Romana R Gerner
- Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology and Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria
| | - Verena Wieser
- Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology and Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology and Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.
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30
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Chang SY, Kim DB, Ko SH, Jang HJ, Jo YH, Kim MJ. The level of nitric oxide regulates lipocalin-2 expression under inflammatory condition in RINm5F beta-cells. Biochem Biophys Res Commun 2016; 476:7-14. [DOI: 10.1016/j.bbrc.2016.05.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 05/22/2016] [Indexed: 02/03/2023]
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31
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Luo Y, Ma X, Pan X, Xu Y, Xiong Q, Xiao Y, Bao Y, Jia W. Serum lipocalin-2 levels are positively associated with not only total body fat but also visceral fat area in Chinese men. Medicine (Baltimore) 2016; 95:e4039. [PMID: 27472678 PMCID: PMC5265815 DOI: 10.1097/md.0000000000004039] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Serum lipocalin-2 (LCN2) plays an important role in the regulation of the obesity-associated dysmetabolic state and cardiovascular disease. However, relatively little is known about the relationship between serum LCN2 levels and body fat content and distribution. We examined the associations of total body fat content and abdominal fat distribution with serum LCN2 levels in Chinese men.The study was based on a cross-sectional analysis of data for 1203 Chinese men aged 22 to 78 years from the Shanghai Obesity Study. Body fat percentage (fat%) was assessed by bioelectrical impedance analysis, and magnetic resonance imaging was adopted to quantify the visceral fat area (VFA) and subcutaneous fat area (SFA). Serum levels of LCN2 were measured with a standard enzyme-linked immunosorbent assay method.Subjects with a high fat% had higher serum LCN2 levels than those with a normal fat% regardless of their body mass index category (<25 and ≥25 kg/m). The frequency of isolated high VFA was increased with increasing quintiles of serum LCN2 levels (P < 0.001), but the frequency of isolated high SFA did not differ between quintiles of serum LCN2 levels. A trend of increasing VFA was observed with increasing serum LCN2 levels (P < 0.001). Multiple stepwise regression analysis showed that VFA was positively associated with serum LCN2 levels, independent of overall obesity and other confounding factors (standardized β = 0.082, P = 0.008).Serum LCN2 levels are positively correlated with body fat content and independently associated with VFA in Chinese men.
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Affiliation(s)
- Yuqi Luo
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Xiaojing Ma
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Xiaoping Pan
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Yiting Xu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Qin Xiong
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Yunfeng Xiao
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yuqian Bao
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
- Correspondence: Prof Yuqian Bao, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China (e-mail: )
| | - Weiping Jia
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
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32
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Kang S, Tsai LT, Zhou Y, Evertts A, Xu S, Griffin MJ, Issner R, Whitton HJ, Garcia BA, Epstein CB, Mikkelsen TS, Rosen ED. Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis. Nat Cell Biol 2015; 17:44-56. [PMID: 25503565 PMCID: PMC4281178 DOI: 10.1038/ncb3080] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 11/06/2014] [Indexed: 02/06/2023]
Abstract
Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.
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Affiliation(s)
- Sona Kang
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
| | - Linus T Tsai
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
| | - Yiming Zhou
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
| | - Adam Evertts
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Su Xu
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
| | - Michael J Griffin
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
| | - Robbyn Issner
- Broad Institute, Cambridge, Massachusetts 02142, USA
| | | | - Benjamin A Garcia
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | | | | | - Evan D Rosen
- 1] Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Broad Institute, Cambridge, Massachusetts 02142, USA [3] Harvard Medical School, Boston, Massachusetts 02215, USA
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Wu G, Li H, Zhou M, Fang Q, Bao Y, Xu A, Jia W. Mechanism and clinical evidence of lipocalin-2 and adipocyte fatty acid-binding protein linking obesity and atherosclerosis. Diabetes Metab Res Rev 2014; 30:447-56. [PMID: 24214285 DOI: 10.1002/dmrr.2493] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 10/29/2013] [Indexed: 12/19/2022]
Abstract
Obesity is considered to be a chronic inflammatory state in which the dysfunction of adipose tissue plays a central role. The adipokines, which are cytokines secreted by adipose tissue, are key links between obesity and related diseases such as metabolic syndrome and atherosclerosis. LCN2 and A-FABP, both of which are major adipokines predominantly produced in adipose tissue, have recently been shown to be pivotal modulators of vascular function. However, different adipokines modulate the development of atherosclerosis in distinctive manners, which are partly attributable to their unique regulatory mechanisms and functions. This review highlights recent advances in the understanding of the role of two adipokines in mediating chronic inflammation and the pathogenesis of atherosclerosis.
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Affiliation(s)
- Guangyu Wu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, China; Department of Medicine, Medical School of Soochow University, Suzhou, China
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Moreno-Navarrete JM, Fernández-Real JM. The possible role of antimicrobial proteins in obesity-associated immunologic alterations. Expert Rev Clin Immunol 2014; 10:855-66. [DOI: 10.1586/1744666x.2014.911088] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abstract
There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function. The past few years, in particular, have seen significant changes in the way that we classify adipocytes and how we view adipose development and differentiation. We have new perspective on the roles played by adipocytes in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues. Finally, there has been significant progress in understanding how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.
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Affiliation(s)
- Evan D Rosen
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Departments of Genetics and Cell Biology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
| | - Bruce M Spiegelman
- Departments of Genetics and Cell Biology, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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Alwahsh SM, Xu M, Seyhan HA, Ahmad S, Mihm S, Ramadori G, Schultze FC. Diet high in fructose leads to an overexpression of lipocalin-2 in rat fatty liver. World J Gastroenterol 2014; 20:1807-1821. [PMID: 24587658 PMCID: PMC3930979 DOI: 10.3748/wjg.v20.i7.1807] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 09/13/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore lipocalin-2 (LCN-2) expression and its possible role and mechanism(s) of production in rat models of diet-inducible fatty liver.
METHODS: Fatty liver was triggered in male Sprague-Dawley rats fed either with liquid Lieber-DeCarli (LDC) or LDC + 70% cal fructose (L-HFr) diet for 4 or 8 wk. Chow-nourished animals served as controls. Hepatic expression of LCN-2 and other metabolic and inflammatory mediators was assessed by quantitative reverse transcription polymerase chain reaction and Western blotting. Serum LCN-2, fasting leptin, and lipid profile were evaluated via Enzyme-Linked Immunosorbent Assay, Radioimmunoassay, and colorimetric assays, respectively. The localization of LCN-2 in the liver was detected by using immunofluorescence staining. Furthermore, HE stain was used to evaluate hepatic fat degeneration and inflammation.
RESULTS: Both LDC-fed and L-HFr-fed rat histologically featured fatty liver. In the liver, mRNA transcriptions of Mcp-1, a2-m, Il-8 and Glut5 were increased in the L-HFr group at both time points (P < 0.001), while the transcription of Tlr4, Inos, and Tnf-α was significantly up-regulated at week 4. Interestingly, hepatic Lcn-2 expression was 90-fold at week 4 and 507-fold at week 8 higher in L-HFr-subjected rats vs control (P < 0.001). In contrast to HDL-cholesterol, systemic levels of LCN-2, fasting leptin and triglycerides were elevated in the L-HFr regimen (P < 0.001). Moreover, protein expression of hepatic LCN-2, CD14, phospho-MAPK, caspase-9, cytochrome c and 4-hydroxynonenal was increased in the L-HFr group. Conversely, the hepatic expression of PGC-1α (a mitochondrial-biogenic protein) was reduced in the L-HFr category at week 8. The localization of LCN-2 in the liver was predominantly restricted to MPO+ granulocytes.
CONCLUSION: Fructose diet up-regulates hepatic LCN-2 expression, which correlates with the increased indicators of oxidative stress and mitochondrial dysfunction. The LCN-2 may be involved in liver protection.
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Friedlander NJ, Burhans MS, Ade L, O'Neill LM, Chen X, Ntambi JM. Global deletion of lipocalin 2 does not reverse high-fat diet-induced obesity resistance in stearoyl-CoA desaturase-1 skin-specific knockout mice. Biochem Biophys Res Commun 2014; 445:578-83. [PMID: 24548407 DOI: 10.1016/j.bbrc.2014.02.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 02/08/2014] [Indexed: 11/29/2022]
Abstract
Over the past century, obesity has developed into a paramount health issue that affects millions of people worldwide. Obese individuals have an increased risk to develop other metabolic disorders, such as insulin resistance and atherosclerosis, among others. Previously we determined that mice lacking stearoyl-CoA desaturase-1 (SCD1) enzyme specifically in the skin (SKO) were lean and protected from high-fat diet induced adiposity. Additionally, lipocalin 2 (Lcn2) mRNA was found to be 27-fold higher in the skin of SKO mice compared to control mice. Given reports suggesting that Lcn2 plays a role in protection against diet-induced weight gain, adiposity and insulin resistance, we hypothesized that deletion of Lcn2 alongside the skin-specific SCD1 deficiency would diminish the obesity resistance observed in SKO mice. To test this, we developed mice lacking SCD1 expression in the skin and also lacking Lcn2 expression globally and surprisingly, these mice did not gain significantly more weight than the SKO mice under high-fat diet conditions. Therefore, we conclude that Lcn2 does not mediate the protection against high-fat diet-induced adiposity observed in SKO mice.
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Affiliation(s)
- Nicholas J Friedlander
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States
| | - Maggie S Burhans
- Department of Nutritional Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States
| | - Lacmbouh Ade
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States
| | - Lucas M O'Neill
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States
| | - Xiaoli Chen
- Department of Food Science and Nutrition, University of Minnesota-Twin Cities, St. Paul, MN 55108, United States
| | - James M Ntambi
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States; Department of Nutritional Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States.
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Zhao P, Elks CM, Stephens JM. The induction of lipocalin-2 protein expression in vivo and in vitro. J Biol Chem 2014; 289:5960-9. [PMID: 24391115 DOI: 10.1074/jbc.m113.532234] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Lipocalin-2 (LCN2) is secreted from adipocytes, and its expression is up-regulated in obese and diabetic mice and humans. LCN2 expression and secretion have been shown to be induced by two proinflammatory cytokines, IFNγ and TNFα, in cultured murine and human adipocytes. In these studies, we demonstrated that IFNγ and TNFα induced LCN2 expression and secretion in vivo. Although we observed a strong induction of LCN2 expression and secretion from white adipose tissue (WAT) depots, the induction of LCN2 varied among different insulin-sensitive tissues. Knockdown experiments also demonstrated that STAT1 is required for IFNγ-induced lipocalin-2 expression in murine adipocytes. Similarly, knockdown of p65 in adipocytes demonstrated the necessity of the NF-κB signaling pathway for TNFα-mediated effects on LCN2. Activation of ERKs by IFNγ and TNFα also affected STAT1 and NF-κB signaling through modulation of serine phosphorylation. ERK activation-induced serine phosphorylation of both STAT1 and p65 mediated the additive effects of IFNγ and TNFα on LCN2 expression. Our results suggest that these same mechanisms occur in humans as we observed STAT1 and NF-κB binding to the human LCN2 promoter in chromatin immunoprecipitation assays performed in human fat cells. These studies substantially increase our knowledge regarding the requirements and mechanisms used by proinflammatory cytokines to induce LCN2 expression.
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Affiliation(s)
- Peng Zhao
- From the Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 and Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808
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Paton CM, Rogowski MP, Kozimor AL, Stevenson JL, Chang H, Cooper JA. Lipocalin-2 increases fat oxidation in vitro and is correlated with energy expenditure in normal weight but not obese women. Obesity (Silver Spring) 2013; 21:E640-8. [PMID: 23640923 DOI: 10.1002/oby.20507] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 04/24/2013] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The role of lipocalin-2 (Lcn2) was determined in regulating metabolism in cell, animal, and human models. DESIGN AND METHODS Adipocytes were treated with recombinant lipocalin-2 (rLcn2) to determine the effect on lipid metabolism. rLcn2 was injected into mice to determine the effect on metabolism in vivo. To assess the relationship between Lcn2 and fat oxidation (FatOx) in humans, normal weight (NW) and obese (OB) women were given three separate high fat (HF) meals followed by indirect calorimetry. The relationship between postprandial Lcn2 with macronutrient metabolism and total energy expenditure (TEE) using Pearson correlations was determined. RESULTS Lcn2 increased expression of genes involved in β-oxidation including peroxisome proliferator-activated receptor-δ in adipocytes, as well as (3) H labeled oleate β-oxidation. Lcn2 injected into chow-fed mice directly increased TEE by 18% after the first dark cycle (232 ± 1.4 cal vs. 341 ± 1.4 cal; PBS vs. Lcn2) and remained significantly elevated by 10% after the second dark cycle (296 ± 1.4 cal vs. 326 ± 1.4 cal; PBS vs. Lcn2). Lcn2 was correlated with TEE in all three HF meal challenges in NW but not OB females. CONCLUSIONS Lipocalin-2 is a novel adipokine that promotes FatOx and TEE and its function may be impaired in obesity.
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Affiliation(s)
- Chad M Paton
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
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Heilbronn LK, Campbell LV, Xu A, Samocha-Bonet D. Metabolically protective cytokines adiponectin and fibroblast growth factor-21 are increased by acute overfeeding in healthy humans. PLoS One 2013; 8:e78864. [PMID: 24205333 PMCID: PMC3799638 DOI: 10.1371/journal.pone.0078864] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 09/24/2013] [Indexed: 12/11/2022] Open
Abstract
CONTEXT Circulating levels of metabolically protective and adverse cytokines are altered in obese humans and rodent models. However, it is not clear whether these cytokines are altered rapidly in response to over-nutrition, or as a later consequence of the obese state. METHODS Forty sedentary healthy individuals were examined prior to and at 3 and 28 days of high fat overfeeding (+1250 kCal/day, 45% fat). Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), adiposity, serum levels of adiponectin and fibroblast growth factor-21 (FGF21), fatty acid binding protein-4 (FABP4), lipocalin-2 and plasminogen activator factor-1 (PAI1) were assessed. Statistics were performed by repeated measures ANOVA. RESULTS Overfeeding increased weight, body fat and liver fat, fasting glucose, insulin and reduced insulin sensitivity by clamp (all P <0.05). Metabolically protective cytokines, adiponectin and FGF21 were increased at day 3 of overfeeding (P ≤0.001) and adiponectin was also elevated at day 28 (P=0.001). FABP4, lipocalin-2 and PAI-1 were not changed by overfeeding at either time point. CONCLUSION Metabolically protective cytokines, adiponectin and FGF-21, were increased by over nutrition and weight gain in healthy humans, despite increases in insulin resistance. We speculate that this was in attempt to maintain glucose homeostasis in a state of nutritional excess. PAI-I, FABP4 and lipocalin 2 were not altered by overfeeding suggesting that changes in these cytokines may be a later consequence of the obese state. CLINICAL TRIAL REGISTRATION www.clinicaltrials.gov (NCT00562393).
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Affiliation(s)
- Leonie K. Heilbronn
- Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
- Research Center for Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
- * E-mail:
| | - Lesley V. Campbell
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Aimin Xu
- Department of Medicine, Department of Pharmacology and Pharmacy, and Research Center of Heart, Brain, Hormone and Healthy Ageing, University of Hong Kong, Hong Kong
| | - Dorit Samocha-Bonet
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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STAT1, NF-κB and ERKs play a role in the induction of lipocalin-2 expression in adipocytes. Mol Metab 2013; 2:161-70. [PMID: 24049731 DOI: 10.1016/j.molmet.2013.04.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Revised: 04/18/2013] [Accepted: 04/19/2013] [Indexed: 11/22/2022] Open
Abstract
Lipocalin-2 (LCN2) is induced in conditions of obesity and Type 2 diabetes (T2DM). IFNγ and TNFα induce LCN2 expression in adipocytes in a manner that is dependent on transcription. The effects of these cytokines are additive. IFNγ induced STAT1 and TNFα induced NF-κB play a role in the induction of LCN2. In the LCN2 promoter, one NF-κB binding site and four STAT1 binding sites were identified by in silico and in vitro approaches. MAPK (ERKs 1 and 2) activation was required for the IFNγ and TNFα induction of LCN2 expression, but did not affect the nuclear translocation or DNA binding activity of STAT1 or NF-κB. The NF-κB binding site and the STAT1 binding sites we identified in vitro were confirmed by in vivo studies. Transfection of a LCN2 promoter/luciferase reporter construct confirmed acute activation by IFNγ and TNFα. Our studies identify mechanisms involved in the actions of cytokines secreted from immune cells in adipose tissue that induce LCN2 expression in conditions of obesity and T2DM.
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Induction mechanism of lipocalin-2 expression by co-stimulation with interleukin-1β and interferon-γ in RINm5F beta-cells. Biochem Biophys Res Commun 2013; 434:577-83. [PMID: 23583381 DOI: 10.1016/j.bbrc.2013.03.117] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 03/27/2013] [Indexed: 11/20/2022]
Abstract
Lipocalin-2 (LCN-2) was known to play a role in obesity and insulin resistance, however, little is known about the expression of LCN-2 in pancreatic islet β-cells. We examined the molecular mechanisms by which proinflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ) induce LCN-2 expression in RINm5F β-cells. IL-1β significantly induced LCN-2 expression while IFN-γ alone did not induce it. IFN-γ significantly potentiated IL-1β-induced LCN-2 protein and mRNA expression. However, promoter study and EMSA showed that IFN-γ failed to potentiate IL-1β-induced LCN-2 promoter activity and binding activity of transcription factors on LCN-2 promoter. Furthermore, LCN-2 mRNA stability and transcription factors NF-κB and STAT-1 were not involved in the stimulatory effect of IFN-γ on IL-1β-induced LCN-2 expression. Meanwhile, Western Blot and promoter analyses showed that NF-κB was a key factor in IL-1β-induced LCN-2 expression. Collectively, IL-1β induces LCN-2 expression via NF-κB activation in RINm5F β-cells. IFN-γ potentiates IL-1β-induced LCN-2 expression at mRNA and protein levels, but not at promoter level and the stimulatory effect of IFN-γ is independent of NF-κB and STAT-1 activation. These data suggest that LCN-2 may play a role in β-cell function under an inflammatory condition.
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Zhou Y, Rui L. Lipocalin 13 regulation of glucose and lipid metabolism in obesity. VITAMINS AND HORMONES 2013; 91:369-83. [PMID: 23374724 DOI: 10.1016/b978-0-12-407766-9.00015-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Lipocalin (LCN) family members are small secreted proteins that bind to small hydrophobic molecules via their characteristic central β-barrels. A couple of LCN family members, including major urinary protein 1, retinol-binding protein 4, LCN2, and LCN13, have been reported to regulate insulin sensitivity and nutrient metabolism. LCN13 is expressed by multiple tissues, including the liver, pancreas, epididymis, and skeletal muscle, and is secreted into the bloodstream in mice. Obesity is associated with a downregulation of LCN13 expression and lower levels of circulating LCN13. LCN13 therapies overcome LCN13 deficiency in mice with either genetic or dietary obesity, leading to an improvement in hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, and hepatic steatosis. In hepatocytes, LCN13 directly suppresses hepatic gluconeogenesis and lipogenesis but increases fatty acid β oxidation. LCN13 also enhances insulin sensitivity in adipocytes. The potential mechanisms of the antidiabetes and antisteatosis actions of LCN13 are discussed.
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Affiliation(s)
- Yingjiang Zhou
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Affiliation(s)
- Susan K Fried
- Division of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, 650 Albany Street, X815, Boston, Massachusetts 02118, USA.
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Guo H, Zhang Y, Brockman DA, Hahn W, Bernlohr DA, Chen X. Lipocalin 2 deficiency alters estradiol production and estrogen receptor signaling in female mice. Endocrinology 2012; 153:1183-93. [PMID: 22234464 PMCID: PMC3281525 DOI: 10.1210/en.2011-1642] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
We have previously characterized lipocalin 2 (Lcn2) as a new adipokine having a critical role in energy and lipid metabolism in male mice. Previous studies by others have suggested that Lcn2 is a putative target gene of estrogens. In this study, we reported the effect of Lcn2 deficiency on estradiol biosynthesis and estrogen receptor signaling in female Lcn2-deficient (Lcn2-/-) mice. We found that Lcn2 expression in white adipose tissue is gender, depot, and age dependent. In female mice, Lcn2 is predominantly expressed in inguinal adipose tissue but at relatively very low levels in perigonadal depot and ovary. After 22 wk of high-fat diet (HFD) feeding or at old age, Lcn2-/- female mice had significantly reduced levels of serum 17β-estradiol and down-regulated expression of estrogen receptor α in multiple metabolic tissues. Consistently, the expression of estrogen-regulated genes involved in cholesterol homeostasis, such as liver X receptor β and low-density lipoprotein receptor was also down-regulated in the adipose tissue of Lcn2-/- mice. These changes were in line with the development of atherogenic dyslipidemia in response to HFD feeding; female Lcn2-/- mice had significantly elevated levels of total cholesterol and low-density lipoprotein cholesterol, whereas reduced high-density lipoprotein cholesterol levels compared with wild-type female mice. Interestingly, when compared with wild-type controls, HFD-fed female Lcn2-/- mice had significantly reduced expression levels of aromatase, a key enzyme regulating estradiol biosynthesis, in adipose tissue. Moreover, Lcn2 deficiency markedly blunted age-related increase in adipose aromatase expression but had no significant impact on age-related reduction in ovarian aromatase expression. Our findings suggest that Lcn2 has a tissue-specific role in adipose estradiol biosynthesis, which may link Lcn2 to obesity- and age-related estradiol production and metabolic complications in females.
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Affiliation(s)
- Hong Guo
- Department of Food Science and Nutrition, University of Minnesota-Twin Cities, St. Paul, Minnesota 55108-1038, USA
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Huang Y, Yang Z, Ye Z, Li Q, Wen J, Tao X, Chen L, He M, Wang X, Lu B, Zhang Z, Zhang W, Qu S, Hu R. Lipocalin-2, glucose metabolism and chronic low-grade systemic inflammation in Chinese people. Cardiovasc Diabetol 2012; 11:11. [PMID: 22292925 PMCID: PMC3295671 DOI: 10.1186/1475-2840-11-11] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 01/31/2012] [Indexed: 12/28/2022] Open
Abstract
Background Lipocalin-2 is a novel adipokine with connection to insulin resistance. In this study, we aimed to investigate the association of serum lipocalin-2 with glucose metabolism and other metabolic phenotype in a large-scale Chinese population. Methods We evaluated serum lipocalin-2 in a cross-sectional sample of 2519 Chinese aged from 50 to 82 year in a Shanghai downtown district by ELISA. Glucose, insulin, lipid profile, inflammatory markers, and adipokines were also measured. Results Serum lipocalin-2 was significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and newly-diagnosed type 2 diabetes than in those with normal glucose regulation. Lipocalin-2 elevation was clearly associated with a higher risk for impaired glucose regulation (OR 1.30 for each 10 ng/ml increase in serum lipocalin-2, 95% CI 1.23-1.62, p = 0.009) after adjustment of age, gender, smoking, alcohol drinking, family history of diabetes, serum CRP, serum adiponectin, serum CXCL5, HOMA-IR, BMI, and waist/hip ratio. The OR for participants with impaired glucose regulation and type 2 diabetes was 1.31 (95% CI 1.21-1.69, p < 0.001). Conclusions Our findings suggest that elevated serum lipocalin-2 is closely and independently associated with impaired glucose regulation and type 2 diabetes.
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Affiliation(s)
- Ying Huang
- Institute of Endocrinology and Diabetology, Huashan hospital, Shanghai Medical College, Fudan University, Shanghai, China
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Abstract
Adipose tissue plays a central role in body weight homeostasis, inflammation, and insulin resistance via serving as a fat-buffering system, regulating lipid storage and mobilization and releasing a large range of adipokines and cytokines. Adipose tissue is also the major inflammation-initiated site in obesity. Adipose-derived adipokines and cytokines are known to be involved in the modulation of a wide range of important physiological processes, particularly immune response, glucose and lipid homeostasis and insulin resistance. Adipose tissue dysfunction, characterized by an imbalanced secretion of pro- and anti-inflammatory adipokines and cytokines, decreased insulin-stimulated glucose uptake, dysregulation of lipid storage and release and mitochondrial dysfunction, has been linked to obesity and its associated metabolic disorders. Proteomic technology has been a powerful tool for identifying key components of the adipose proteome, which may contribute to the pathogenesis of adipose tissue dysfunction in obesity. In this review, we summarized the recent advances in the proteomic characterization of adipose tissue and discussed the identified proteins that potentially play important roles in insulin resistance and lipid homeostasis.
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