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Zheng Q, Deng S, Chen X, Wang Y, Yang Y. Macrophage inhibition in the alleviation of nonalcoholic steatohepatitis caused by bariatric surgery. Genes Immun 2025:10.1038/s41435-025-00334-6. [PMID: 40374920 DOI: 10.1038/s41435-025-00334-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 04/21/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025]
Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, and effective treatment is urgently needed. To understand the molecular mechanisms behind the effectiveness of bariatric surgery in treating NASH, we integrated single-cell and bulk RNA sequencing data to identify the role of liver macrophage polarization in alleviating NASH and screen possible drugs for treatment. Analysis revealed that bariatric surgery alleviates NASH by inhibiting liver M1 macrophage polarization with 12 differentially expressed M1 macrophage-related genes. Additionally, 56 potentially effective drugs were predicted for NASH treatment. These findings shed light on the effectiveness of bariatric surgery in treating NASH and offer potential drug candidates for further exploration.
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Affiliation(s)
- Qianwen Zheng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Shizhou Deng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xiyu Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yayun Wang
- Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China.
| | - Yanling Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
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Cálix M, Menéndez R, Baley M, Cadena A, Carrillo C, García-Jiménez J. Histological Changes in Skin and Subcutaneous Cellular Tissue in Patients with Massive Weight Loss After Bariatric Surgery. Aesthetic Plast Surg 2024; 48:5060-5066. [PMID: 39313664 DOI: 10.1007/s00266-024-04376-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024]
Abstract
INTRODUCTION Morbid obesity is a public health problem with high social and economic impact. Due to failure in its treatment with traditional weight loss strategies, surgical interventions are usually required, which give rise to massive weight loss. Until now, the studies made are inconclusive regarding the histological changes in the skin caused by massive weight loss, which may later generate post-surgical complications. Therefore, the objective of this study is to evaluate the cutaneous histological changes before and after bariatric surgery. MATERIAL AND METHODS Two skin biopsies were taken from nine different patients who underwent bariatric surgery. The first biopsy was taken before the surgical intervention, and the second biopsy was taken a year after the surgery and massive weight loss. Histological analysis was performed using haematoxylin & eosin staining, Weigert's Resorcin-Fuchsin, and Masson's trichrome stain to analyse the percentage of collagen fibres, percentage of fibrosis, percentage of vascularity, vascular layer involvement and adipocyte population. The differences between the biopsies were evaluated with the Student's T test and Mann-Whitney U test, with a p-value of <0.05. RESULTS Biopsies from post-bariatric patients with MWL showed an increase in fibrosis percentage, and a decrease in collagen fibres, elastic fibres of the dermis, adipocyte population, as well as reduced vascular proliferation. CONCLUSION MWL after bariatric surgery gives rise to changes in the skin and subcutaneous cellular tissue. Skin shows an increased fibrosis percentage after massive weight loss. Elastic and collagen fibres become disorganized after massive weight loss. Vascular proliferation is decreased after massive weight loss. LEVEL OF EVIDENCE IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Miguel Cálix
- Servicio de Cirugía Plástica y Reconstructiva, Centro Médico ISSEMyM. Estado de Mexico, Mexico. Av. Baja Velocidad 284, km 57.5, San Jerónimo Chicahualco, Metepec, Estado de, Mexico.
| | - Rodrigo Menéndez
- Servicio de Cirugía Plástica y Reconstructiva, Centro Médico ISSEMyM. Estado de Mexico, Mexico. Av. Baja Velocidad 284, km 57.5, San Jerónimo Chicahualco, Metepec, Estado de, Mexico
| | - Mauricio Baley
- Servicio de Cirugía Plástica y Reconstructiva, Centro Médico ISSEMyM. Estado de Mexico, Mexico. Av. Baja Velocidad 284, km 57.5, San Jerónimo Chicahualco, Metepec, Estado de, Mexico
| | - Alberto Cadena
- Servicio de Cirugía Plástica y Reconstructiva, Centro Médico ISSEMyM. Estado de Mexico, Mexico. Av. Baja Velocidad 284, km 57.5, San Jerónimo Chicahualco, Metepec, Estado de, Mexico
| | - Claudia Carrillo
- Servicio de Patología, Centro Médico ISSEMyM. Estado de Mexico, Mexico. Av. Baja Velocidad 284, km 57.5, San Jerónimo Chicahualco, Metepec, Estado de, Mexico
| | - Jafet García-Jiménez
- Facultad de Medicina, Universidad Autónoma del Estado de México, Av. Paseo Tollocan S/N, esq. Jesús Carranza, Col. Moderna de la Cruz, 50180, Toluca de Lerdo, Mexico
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Kuziel G, Moore BN, Haugstad GP, Xiong Y, Williams AE, Arendt LM. Alterations in the mammary gland and tumor microenvironment of formerly obese mice. BMC Cancer 2023; 23:1183. [PMID: 38041006 PMCID: PMC10693119 DOI: 10.1186/s12885-023-11688-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/28/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. Weight loss is a recommended intervention to resolve obesity, but the impact of weight loss on the mammary gland microenvironment and in tumors has not been well identified. METHODS To examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells. RESULTS In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells. CONCLUSIONS Overall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.
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Affiliation(s)
- Genevra Kuziel
- Cancer Biology Program, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Brittney N Moore
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Grace P Haugstad
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Yue Xiong
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Abbey E Williams
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Lisa M Arendt
- Cancer Biology Program, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, USA.
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison, WI, 53706, USA.
- School of Veterinary Medicine, 2015 Linden Drive Rm 4354A, Madison, WI, 53706, USA.
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Alves DVL, Claudio-da-Silva C, Souza MCA, Pinho RT, da Silva WS, Sousa-Vasconcelos PS, Borojevic R, Nogueira CM, Dutra HDS, Takiya CM, Bonfim DC, Rossi MID. Adipose Tissue-Derived Mesenchymal Stromal Cells from Ex-Morbidly Obese Individuals Instruct Macrophages towards a M2-Like Profile In Vitro. Int J Stem Cells 2023; 16:425-437. [PMID: 37643763 PMCID: PMC10686802 DOI: 10.15283/ijsc22172] [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: 10/12/2022] [Revised: 03/21/2023] [Accepted: 04/04/2023] [Indexed: 08/31/2023] Open
Abstract
Obesity, which continues to increase worldwide, was shown to irreversibly impair the differentiation potential and angiogenic properties of adipose tissue mesenchymal stromal cells (ADSCs). Because these cells are intended for regenerative medicine, especially for the treatment of inflammatory conditions, and the effects of obesity on the immunomodulatory properties of ADSCs are not yet clear, here we investigated how ADSCs isolated from former obese subjects (Ex-Ob) would influence macrophage differentiation and polarization, since these cells are the main instructors of inflammatory responses. Analysis of the subcutaneous adipose tissue (SAT) of overweight (OW) and Ex-Ob subjects showed the maintenance of approximately twice as many macrophages in Ex-Ob SAT, contained within the CD68＋/FXIII-A- inflammatory pool. Despite it, in vitro, coculture experiments revealed that Ex-Ob ADSCs instructed monocyte differentiation into a M2-like profile, and under inflammatory conditions induced by LPS treatment, inhibited HLA-DR upregulation by resting M0 macrophages, originated a similar percentage of TNF-α＋ cells, and inhibited IL-10 secretion, similar to OW-ADSCs and BMSCs, which were used for comparison, as these are the main alternative cell types available for therapeutic purposes. Our results showed that Ex-Ob ADSCs mirrored OW-ADSCs in macrophage education, favoring the M2 immunophenotype and a mixed (M1/M2) secretory response. These results have translational potential, since they provide evidence that ADSCs from both Ex-Ob and OW subjects can be used in regenerative medicine in eligible therapies. Further in vivo studies will be fundamental to validate these observations.
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Affiliation(s)
- Daiana V. Lopes Alves
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Integrated Laboratory of Morphology, Institute of Biodiversity and Sustainability, NUPEM, Federal University of Rio de Janeiro, Macaé, RJ, Brazil
| | - Cesar Claudio-da-Silva
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Surgery Department, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Marcelo C. A. Souza
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Surgery Department, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Rosa T. Pinho
- Laboratory of Clinical Immunology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
| | | | | | - Radovan Borojevic
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Carmen M. Nogueira
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Hélio dos S. Dutra
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Christina M. Takiya
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Danielle C. Bonfim
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Maria Isabel D. Rossi
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Kuziel G, Moore BN, Haugstad GP, Xiong Y, Williams AE, Arendt LM. Alterations in the Mammary Gland and Tumor Microenvironment of Formerly Obese Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.14.545000. [PMID: 37398468 PMCID: PMC10312750 DOI: 10.1101/2023.06.14.545000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. To examine the impact of weight loss on the mammary microenvironment, mice were fed high-fat diet to induce obesity, then switched to a low-fat diet. In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, collagen deposition within the tumors was significantly greater compared to when tumor cells were mixed with CD11b+CD34- monocytes, suggesting that fibrocytes contribute to early collagen deposition in mammary tumors of obese mice. Overall, these studies show that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression.
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Affiliation(s)
- Genevra Kuziel
- Cancer Biology Program, University of Wisconsin-Madison, Madison WI 53705, U.S.A
| | - Brittney N. Moore
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison WI 53706, U.S.A
| | - Grace P. Haugstad
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison WI 53706, U.S.A
| | - Yue Xiong
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison WI 53706, U.S.A
| | - Abbey E. Williams
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison WI 53706, U.S.A
| | - Lisa M. Arendt
- Cancer Biology Program, University of Wisconsin-Madison, Madison WI 53705, U.S.A
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison WI 53706, U.S.A
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison WI 53706, U.S.A
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Kuziel G, Moore BN, Arendt LM. Obesity and Fibrosis: Setting the Stage for Breast Cancer. Cancers (Basel) 2023; 15:cancers15112929. [PMID: 37296891 DOI: 10.3390/cancers15112929] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Obesity is a rising health concern and is linked to a worsened breast cancer prognosis. Tumor desmoplasia, which is characterized by elevated numbers of cancer-associated fibroblasts and the deposition of fibrillar collagens within the stroma, may contribute to the aggressive clinical behavior of breast cancer in obesity. A major component of the breast is adipose tissue, and fibrotic changes in adipose tissue due to obesity may contribute to breast cancer development and the biology of the resulting tumors. Adipose tissue fibrosis is a consequence of obesity that has multiple sources. Adipocytes and adipose-derived stromal cells secrete extracellular matrix composed of collagen family members and matricellular proteins that are altered by obesity. Adipose tissue also becomes a site of chronic, macrophage-driven inflammation. Macrophages exist as a diverse population within obese adipose tissue and mediate the development of fibrosis through the secretion of growth factors and matricellular proteins and interactions with other stromal cells. While weight loss is recommended to resolve obesity, the long-term effects of weight loss on adipose tissue fibrosis and inflammation within breast tissue are less clear. Increased fibrosis within breast tissue may increase the risk for tumor development as well as promote characteristics associated with tumor aggressiveness.
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Affiliation(s)
- Genevra Kuziel
- Cancer Biology Graduate Program, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA
| | - Brittney N Moore
- Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA
| | - Lisa M Arendt
- Cancer Biology Graduate Program, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA
- Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA
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Li Y, Lee SH, Piao M, Kim HS, Lee KY. Metallothionein 3 Inhibits 3T3-L1 Adipocyte Differentiation via Reduction of Reactive Oxygen Species. Antioxidants (Basel) 2023; 12:antiox12030640. [PMID: 36978888 PMCID: PMC10045306 DOI: 10.3390/antiox12030640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Metallothionein 3 (MT3), also known as a neuronal growth-inhibitory factor, is a member of the metallothionein family and is involved in a variety of biological functions, including protection against metal toxicity and reactive oxygen species (ROS). However, less is known about the role of MT3 in the differentiation of 3T3-L1 cells into adipocytes. In this study, we observed that MT3 levels were downregulated during 3T3-L1 adipocyte differentiation. Mt3 overexpression inhibited adipocyte differentiation and reduced the levels of the adipogenic transcription factors C/EBPα and PPARγ. Further analyses showed that MT3 also suppressed the transcriptional activity of PPARγ, and this effect was not mediated by a direct interaction between MT3 with PPARγ. In addition, Mt3 overexpression resulted in a decrease in ROS levels during early adipocyte differentiation, while treatment with antimycin A, which induces ROS generation, restored the ROS levels. Mt3 knockdown, on the other hand, elevated ROS levels, which were suppressed upon treatment with the antioxidant N-acetylcysteine. Our findings indicate a previously unknown role of MT3 in the differentiation of 3T3-L1 cells into adipocytes and provide a potential novel target that might facilitate obesity treatment.
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Affiliation(s)
- Yuankuan Li
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Sung Ho Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Meiyu Piao
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
- Correspondence: (H.S.K.); (K.Y.L.)
| | - Kwang Youl Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
- Correspondence: (H.S.K.); (K.Y.L.)
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Valadez LZM, Frigolet ME, Dominguez RM, Pescarus R, Zerrweck C, Boudreau V, Doumouras A, Cookson T, Anvari M. Metabolic and Bariatric Surgery in Diabetes Management. THE DIABETES TEXTBOOK 2023:673-690. [DOI: 10.1007/978-3-031-25519-9_42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Camastra S, Palumbo M, Santini F. Nutrients handling after bariatric surgery, the role of gastrointestinal adaptation. Eat Weight Disord 2022; 27:449-461. [PMID: 33895917 PMCID: PMC8933374 DOI: 10.1007/s40519-021-01194-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/10/2021] [Indexed: 01/19/2023] Open
Abstract
Bariatric surgery determines a rearrangement of the gastrointestinal tract that influences nutrient handling and plays a role in the metabolic changes observed after surgery. Most of the changes depend on the accelerated gastric emptying observed in Roux-en-Y gastric bypass (RYGB) and, to a lesser extent, in sleeve gastrectomy (SG). The rapid delivery of meal into the jejunum, particularly after RYGB, contributes to the prompt appearance of glucose in peripheral circulation. Glucose increase is the principal determinant of GLP-1 increase with the consequent stimulation of insulin secretion, the latter balanced by a paradoxical glucagon increase that stimulates EGP to prevent hypoglycaemia. Protein digestion and amino acid absorption appear accelerated after RYGB but not after SG. After RYGB, the adaptation of the gut to the new condition participates to the metabolic change. The intestinal transit is delayed, the gut microbioma is changed, the epithelium becomes hypertrophic and increases the expression of glucose transporter and of the number of cell secreting hormones. These changes are not observed after SG. After RYGB-less after SG-bile acids (BA) increase, influencing glucose metabolism probably modulating FXR and TGR5 with an effect on insulin sensitivity. Muscle, hepatic and adipose tissue insulin sensitivity improve, and the gut reinforces the recovery of IS by enhancing glucose uptake and through the effect of the BA. The intestinal changes observed after RYGB result in a light malabsorption of lipid but not of carbohydrate and protein. In conclusion, functional and morphological adaptations of the gut after RYGB and SG activate inter-organs cross-talk that modulates the metabolic changes observed after surgery.Level of evidence Level V, narrative literature review.
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Affiliation(s)
- Stefania Camastra
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. .,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy.
| | - Maria Palumbo
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy
| | - Ferruccio Santini
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
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10
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M1 Polarized Macrophages Persist in Skin of Post-Bariatric Patients after 2 Years. Aesthetic Plast Surg 2022; 46:287-296. [PMID: 34750657 DOI: 10.1007/s00266-021-02649-x] [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: 07/14/2021] [Accepted: 10/23/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Obesity is considered a condition of systemic chronic inflammation. Under this condition, adipose tissue macrophages switch from an M2 (anti-inflammatory) activation pattern to an M1 (proinflammatory) activation pattern. OBJECTIVE The study aimed to verify the profile of skin macrophage activation after bariatric surgery as well as the role of MMP-1 in extracellular tissue remodeling. METHODS This is a prospective, controlled and comparative study with 20 individuals split into two groups according to their skin condition: post-bariatric and eutrophic patients. Histological and morphometric analyses based on hematoxylin-eosin, picrosirius red (collagen), orcein (elastic fiber systems), and alcian blue (mast cells)-stained sections and immunohistochemical analysis (CD68, iNOS, and mannose receptor) for macrophages and metalloproteinase-1 were performed. RESULTS Post-bariatric skin showed an increase in inflammation, angiogenesis, CD68, M1 macrophages (P< 0.001), and mast cells (P< 0.01); a decrease in M2 macrophages (P< 0.01); and a significant decrease in the collagen fiber network (P< 0.001). MMP-1 was increased in the papillary dermis of post-bariatric skin and decreased in the epidermis compared to eutrophic skin (P< 0.05). CONCLUSION This study shows that post-bariatric skin maintains inflammatory characteristics for two years. Mast cells and M1 macrophages maintain and enhance the remodeling of the dermal extracellular matrix initiated during obesity in part due to the presence of MMP-1 in the papillary dermis. EBM LEVEL IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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11
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Ye RZ, Richard G, Gévry N, Tchernof A, Carpentier AC. Fat Cell Size: Measurement Methods, Pathophysiological Origins, and Relationships With Metabolic Dysregulations. Endocr Rev 2022; 43:35-60. [PMID: 34100954 PMCID: PMC8755996 DOI: 10.1210/endrev/bnab018] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Indexed: 11/19/2022]
Abstract
The obesity pandemic increasingly causes morbidity and mortality from type 2 diabetes, cardiovascular diseases and many other chronic diseases. Fat cell size (FCS) predicts numerous obesity-related complications such as lipid dysmetabolism, ectopic fat accumulation, insulin resistance, and cardiovascular disorders. Nevertheless, the scarcity of systematic literature reviews on this subject is compounded by the use of different methods by which FCS measurements are determined and reported. In this paper, we provide a systematic review of the current literature on the relationship between adipocyte hypertrophy and obesity-related glucose and lipid dysmetabolism, ectopic fat accumulation, and cardiovascular disorders. We also review the numerous mechanistic origins of adipocyte hypertrophy and its relationship with metabolic dysregulation, including changes in adipogenesis, cell senescence, collagen deposition, systemic inflammation, adipokine secretion, and energy balance. To quantify the effect of different FCS measurement methods, we performed statistical analyses across published data while controlling for body mass index, age, and sex.
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Affiliation(s)
- Run Zhou Ye
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Gabriel Richard
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Nicolas Gévry
- Department of Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - André Tchernof
- Québec Heart and Lung Research Institute, Laval University, Québec, Québec, Canada
| | - André C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
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12
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Pincu Y, Yoel U, Haim Y, Makarenkov N, Maixner N, Shaco-Levy R, Bashan N, Dicker D, Rudich A. Assessing Obesity-Related Adipose Tissue Disease (OrAD) to Improve Precision Medicine for Patients Living With Obesity. Front Endocrinol (Lausanne) 2022; 13:860799. [PMID: 35574032 PMCID: PMC9098964 DOI: 10.3389/fendo.2022.860799] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Obesity is a heterogenous condition that affects the life and health of patients to different degrees and in different ways. Yet, most approaches to treat obesity are not currently prescribed, at least in a systematic manner, based on individual obesity sub-phenotypes or specifically-predicted health risks. Adipose tissue is one of the most evidently affected tissues in obesity. The degree of adipose tissue changes - "adiposopathy", or as we propose to relate to herein as Obesity-related Adipose tissue Disease (OrAD), correspond, at least cross-sectionally, to the extent of obesity-related complications inflicted on an individual patient. This potentially provides an opportunity to better personalize anti-obesity management by utilizing the information that can be retrieved by assessing OrAD. This review article will summarize current knowledge on histopathological OrAD features which, beyond cross-sectional analyses, had been shown to predict future obesity-related endpoints and/or the response to specific anti-obesity interventions. In particular, the review explores adipocyte cell size, adipose tissue inflammation, and fibrosis. Rather than highly-specialized methods, we emphasize standard pathology laboratory approaches to assess OrAD, which are readily-available in most clinical settings. We then discuss how OrAD assessment can be streamlined in the obesity/weight-management clinic. We propose that current studies provide sufficient evidence to inspire concerted efforts to better explore the possibility of predicting obesity related clinical endpoints and response to interventions by histological OrAD assessment, in the quest to improve precision medicine in obesity.
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Affiliation(s)
- Yair Pincu
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- Department of Health and Exercise Science, University of Oklahoma, Norman, OK, United States
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Uri Yoel
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- The Endocrinology Service, Soroka University Medical Center, Beer-Sheva, Israel
| | - Yulia Haim
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nataly Makarenkov
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Nitzan Maixner
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Ruthy Shaco-Levy
- Institute of Pathology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nava Bashan
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Dror Dicker
- Department of Internal Medicine D, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel
- *Correspondence: Assaf Rudich, ; Dror Dicker,
| | - Assaf Rudich
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
- *Correspondence: Assaf Rudich, ; Dror Dicker,
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Turner L, Santosa S. Putting ATM to BED: How Adipose Tissue Macrophages Are Affected by Bariatric Surgery, Exercise, and Dietary Fatty Acids. Adv Nutr 2021; 12:1893-1910. [PMID: 33979430 PMCID: PMC8483961 DOI: 10.1093/advances/nmab011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/17/2020] [Accepted: 01/19/2021] [Indexed: 12/20/2022] Open
Abstract
With increasing adiposity in obesity, adipose tissue macrophages contribute to adipose tissue malfunction and increased circulating proinflammatory cytokines. The chronic low-grade inflammation that occurs in obesity ultimately gives rise to a state of metainflammation that increases the risk of metabolic disease. To date, only lifestyle and surgical interventions have been shown to be somewhat effective at reversing the negative consequences of obesity and restoring adipose tissue homeostasis. Exercise, dietary interventions, and bariatric surgery result in immunomodulation, and for some individuals their effects are significant with or without weight loss. Robust evidence suggests that these interventions reduce chronic inflammation, in part, by affecting macrophage infiltration and promoting a phenotypic switch from the M1- to M2-like macrophages. The purpose of this review is to discuss the impact of dietary fatty acids, exercise, and bariatric surgery on cellular characteristics affecting adipose tissue macrophage presence and phenotypes in obesity.
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Affiliation(s)
- Laurent Turner
- Department of Health, Kinesiology, and Applied Physiology, Concordia University, Montreal, Quebec, Canada,Metabolism, Obesity, and Nutrition Lab, PERFORM Centre, Concordia University, Montreal, Quebec, Canada
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RYGB Is More Effective than VSG at Protecting Mice from Prolonged High-Fat Diet Exposure: An Occasion to Roll Up Our Sleeves? Obes Surg 2021; 31:3227-3241. [PMID: 33856636 DOI: 10.1007/s11695-021-05389-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE Understanding the effects of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on adipose tissue physiology is important for the treatment of obesity-related metabolic disorders. By using robust mouse models of bariatric surgery that closely resemble those performed in humans, we can compare the effects of RYGB and VSG on adipose physiology in the absence of post-operative confounds such as diet and lifestyle changes. MATERIALS AND METHODS RYGB and VSG were compared using a diet-induced mouse model of obesity. High-fat diet (HFD) was administered post-operatively and changes to white and brown adipose tissue were evaluated, along with alterations to weight, glucose homeostasis, dyslipidemia, and insulin sensitivity. RESULTS After prolonged exposure to high-fat diet post-operatively, RYGB was effective in achieving sustained weight loss, while VSG unexpectedly accelerated weight gain rates. The resolution of obesity-related comorbidities such as glucose and insulin intolerance, dyslipidemia, and insulin sensitivity was improved after RYGB, but not for VSG. In RYGB, there were improvements to the function and health of white adipose tissue, enhanced brown adipose metabolism, and the browning of subcutaneous white adipose tissue, with no comparable changes seen for these factors after VSG. Some markers of systemic inflammation improved after both RYGB and VSG. CONCLUSION There are significantly different effects between RYGB and VSG when HFD is administered post-operatively and robust mouse models of bariatric surgery are used. RYGB resulted in lasting physiological and metabolic changes but VSG showed little difference from that of its sham-operated, DIO counterpart.
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15
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Madhvi A, Mishra H, Chegou NN, Tromp G, Van Heerden CJ, Pietersen RD, Leisching G, Baker B. Distinct host-immune response toward species related intracellular mycobacterial killing: A transcriptomic study. Virulence 2020; 11:170-182. [PMID: 32052695 PMCID: PMC7051142 DOI: 10.1080/21505594.2020.1726561] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 01/01/2020] [Accepted: 01/03/2020] [Indexed: 01/10/2023] Open
Abstract
The comparison of the host immune response when challenged with pathogenic and nonpathogenic species of mycobacteria can provide answers to the unresolved question of how pathogens subvert or inhibit an effective response. We infected human monocyte derived macrophages (hMDMs) with different species of mycobacteria, in increasing order of pathogenicity, i.e. M. smegmatis, M. bovis BCG, and M. tuberculosis R179 that had been cultured in the absence of detergents. RNA was isolated post-infection and transcriptomic analysis using amplicons (Ampliseq) revealed 274 differentially expressed genes (DEGs) across three species, out of which we selected 19 DEGs for further validation. We used qRT-PCR to confirm the differential expression of 19 DEGs. We studied biological network through Ingenuity Pathway Analysis® (IPA) which revealed up-regulated pathways of the interferon and interleukin family related to the killing of M. smegmatis. Apart from interferon and interleukin family, we found one up-regulated (EIF2AK2) and two down-regulated (MT1A and TRIB3) genes as unique potential targets found by Ampliseq and qRT-PCR which may be involved in the intracellular mycobacterial killing. The roles of these genes have not previously been described in tuberculosis. Multiplex ELISA of culture supernatants showed increased host immune response toward M. smegmatis as compared to M. bovis BCG and M.tb R179. These results enhance our understanding of host immune response against M.tb infection.
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Affiliation(s)
- Abhilasha Madhvi
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Hridesh Mishra
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Novel N. Chegou
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Gerard Tromp
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Tuberculosis Bioinformatics Initiative (SATBBI), Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Centre for Bioinformatics and Computational Biology, Stellenbosch University, Cape Town, South Africa
| | - Carel J. Van Heerden
- DNA Sequencing Unit, Central Analytical Facility (CAF), Stellenbosch University, Stellenbosch, South Africa
| | - R. D. Pietersen
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Gina Leisching
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Bienyameen Baker
- NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Implications of metabolism-driven myeloid dysfunctions in cancer therapy. Cell Mol Immunol 2020; 18:829-841. [PMID: 33077904 PMCID: PMC7570408 DOI: 10.1038/s41423-020-00556-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/10/2020] [Indexed: 02/07/2023] Open
Abstract
Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.
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Zamarron BF, Porsche CE, Luan D, Lucas HR, Mergian TA, Martinez-Santibanez G, Cho KW, DelProposto JL, Geletka LM, Muir LA, Singer K, Lumeng CN. Weight Regain in Formerly Obese Mice Hastens Development of Hepatic Steatosis Due to Impaired Adipose Tissue Function. Obesity (Silver Spring) 2020; 28:1086-1097. [PMID: 32281747 PMCID: PMC7245566 DOI: 10.1002/oby.22788] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/20/2020] [Accepted: 02/04/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Weight regain after weight loss is common, and there is evidence to suggest negative effects on health because of weight cycling. This study sought to investigate the impact of weight regain in formerly obese mice on adipose tissue architecture and stromal cell function. METHODS A diet-switch model was employed for obesity induction, weight loss, and weight regain in mice. Flow cytometry quantified adipose tissue leukocytes in adipose tissue. Liver and adipose tissue depots were compared to determine tissue-specific effects of weight cycling. RESULTS Epididymal white adipose tissue of formerly obese mice failed to expand in response to repeat exposure to high-fat diet and retained elevated numbers of macrophages and T cells. Weight regain was associated with disproportionally elevated liver mass, hepatic triglyceride content, serum insulin concentration, and serum transaminase concentration. These effects occurred despite an extended 6-month weight loss cycle and they demonstrate that formerly obese mice maintain durable alterations in their physiological response to weight regain. Conditioned media from epididymal adipose tissue of formerly obese mice inhibited adipogenesis of 3T3-L1 preadipocytes, suggesting a potential mechanism to explain failed epididymal adipose tissue expansion during weight regain. CONCLUSIONS Metabolic abnormalities related to defects in adipose tissue expansion and ongoing dysfunction manifest in formerly obese mice during weight regain.
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Affiliation(s)
- Brian F Zamarron
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Cara E Porsche
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Danny Luan
- College of Literature Sciences and Arts, University of Michigan, Ann Arbor, Michigan, USA
| | - Hannah R Lucas
- College of Literature Sciences and Arts, University of Michigan, Ann Arbor, Michigan, USA
| | - Taleen A Mergian
- College of Literature Sciences and Arts, University of Michigan, Ann Arbor, Michigan, USA
| | - Gabriel Martinez-Santibanez
- Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Kae Won Cho
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do, Korea
| | - Jennifer L DelProposto
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Lynn M Geletka
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Lindsey A Muir
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Kanakadurga Singer
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Carey N Lumeng
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med 2020; 7:22. [PMID: 32158768 PMCID: PMC7052117 DOI: 10.3389/fcvm.2020.00022] [Citation(s) in RCA: 745] [Impact Index Per Article: 149.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.
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Affiliation(s)
- Alan Chait
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Laura J den Hartigh
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
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Katsogiannos P, Kamble PG, Boersma GJ, Karlsson FA, Lundkvist P, Sundbom M, Pereira MJ, Eriksson JW. Early Changes in Adipose Tissue Morphology, Gene Expression, and Metabolism After RYGB in Patients With Obesity and T2D. J Clin Endocrinol Metab 2019; 104:2601-2613. [PMID: 30689903 DOI: 10.1210/jc.2018-02165] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 01/18/2019] [Indexed: 02/13/2023]
Abstract
CONTEXT Roux-en-Y gastric bypass (RYGB) surgery effectively prevents or treats type 2 diabetes (T2D). Adipose tissue (AT) mechanisms may be of importance. OBJECTIVE To assess the relationship between early changes in whole-body and AT metabolism in surgically treated patients with T2D. DESIGN AND SETTING A randomized single-center study. PATIENTS Nineteen patients with T2D with body mass index 30 to 45 kg/m2. INTERVENTIONS Thirteen patients were assessed at baseline and 4 and 24 weeks after RYGB (preceded by a 4-week low-calorie diet) and compared with 6 control patients continuing standard medical treatment: oral glucose tolerance test, subcutaneous AT biopsies for gene expression, adipocyte size, glucose uptake, lipolysis, and insulin action. RESULTS At 4 and 24 weeks post-RYGB, all patients but one had stopped diabetes medication. Fasting glucose, HbA1c, and insulin levels decreased and the Matsuda index increased compared with baseline (P < 0.01 for all), indicating improved whole-body insulin sensitivity. Mean adipocyte size significantly reduced, more at 4 than at 24 weeks; at 4 weeks, glucose uptake per adipocyte was lowered, and isoproterenol-stimulated lipolysis tended to increase, whereas the fold insulin effects on glucose uptake and lipolysis were unchanged. Expression of genes involved in fatty acid oxidation, CPT1b and adiponectin, was increased at 4 weeks, whereas leptin and E2F1 (involved in cell proliferation) were reduced (P < 0.05 for all). CONCLUSION Glycemic control and in vivo insulin sensitivity improved 4 weeks after RYGB, but adipocyte insulin sensitivity did not change despite a marked reduction in adipocyte size. Thus, mechanisms for a rapid improvement of T2D after RYGB may occur mainly in other tissues than adipose.
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MESH Headings
- Adipocytes/metabolism
- Adult
- Biopsy
- Blood Glucose/analysis
- Blood Glucose/metabolism
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/etiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/surgery
- Female
- Follow-Up Studies
- Gastric Bypass
- Humans
- Insulin/metabolism
- Insulin Resistance
- Male
- Middle Aged
- Obesity, Morbid/blood
- Obesity, Morbid/complications
- Obesity, Morbid/metabolism
- Obesity, Morbid/surgery
- Subcutaneous Fat, Abdominal/cytology
- Subcutaneous Fat, Abdominal/metabolism
- Subcutaneous Fat, Abdominal/pathology
- Treatment Outcome
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Affiliation(s)
| | - Prasad G Kamble
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Gretha J Boersma
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Per Lundkvist
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Magnus Sundbom
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Maria J Pereira
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Griffin C, Hutch CR, Abrishami S, Stelmak D, Eter L, Li Z, Chang E, Agarwal D, Zamarron B, Varghese M, Subbaiah P, MacDougald OA, Sandoval DA, Singer K. Inflammatory responses to dietary and surgical weight loss in male and female mice. Biol Sex Differ 2019; 10:16. [PMID: 30944030 PMCID: PMC6446331 DOI: 10.1186/s13293-019-0229-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Weight loss by surgery or lifestyle changes is strongly recommended for obese individuals to improve metabolic health, but the underlying impairments that persist from a history of obesity remain unclear. Recent investigations demonstrate a persistent inflammatory state with weight loss and bariatric surgery, but the mechanism and impact are not fully understood. Additionally, these studies have not been performed in females although women are the majority of individuals undergoing weight loss interventions. METHODS The goal of this study was to determine the sex differences in metabolically induced inflammation after dietary weight loss (WL) or bariatric surgery. Following a 60% high-fat diet (HFD) for 12 weeks, C57Bl/6j mice underwent either a dietary switch to normal chow for WL or vertical sleeve gastrectomy (VSG) and were evaluated 8 weeks after intervention. WL effects on myelopoiesis were further evaluated with bone marrow chimeras. RESULTS Both sexes had a decrease in adiposity and total weight following WL or VSG intervention. With HFD, females had very little inflammation and no further increase with WL, but males had persistent inflammation even after WL despite metabolic improvement. Interestingly, after VSG, myeloid inflammation was increased in the livers of males and to a lesser extent in females. CONCLUSIONS These studies demonstrate that regardless of sex, it is critical to assess an individuals' history of obesity rather than just rely on current weight status in medical decision-making. There are long-lasting effects on tissue inflammation in both sexes especially with surgical weight loss. Dietary change is overall most effective to improve meta-inflammation in obese males on its own or in combination with surgical weight loss.
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Affiliation(s)
- Cameron Griffin
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Chelsea R Hutch
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Simin Abrishami
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Daria Stelmak
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Leila Eter
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ziru Li
- Department Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Eric Chang
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Devyani Agarwal
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Brian Zamarron
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Mita Varghese
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Perla Subbaiah
- Department of Mathematics and Statistics, Oakland University, Rochester, MI, 48309, USA
| | - Ormond A MacDougald
- Department Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Darleen A Sandoval
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kanakadurga Singer
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA. .,Department of Pediatrics, Division of Pediatric Endocrinology, D1205 MPB, 1500 E Medical Center Dr., Ann Arbor, MI, 48109, USA.
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Chen X, Gong L, Li Q, Hu J, Liu X, Wang Y, Bai J, Ran X, Wu J, Ge Q, Li R, Xiao X, Li X, Zhang J, Wang Z. The appropriate remodeling of extracellular matrix is the key molecular signature in subcutaneous adipose tissue following Roux-en-Y gastric bypass. Life Sci 2019; 218:265-273. [DOI: 10.1016/j.lfs.2018.12.051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/24/2018] [Accepted: 12/29/2018] [Indexed: 12/12/2022]
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Evaluation of metallothioneins, oxidative stress and signs of cytotoxicity in young obese women. UKRAINIAN BIOCHEMICAL JOURNAL 2018. [DOI: 10.15407/ubj90.05.071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice. Biochim Biophys Acta Gen Subj 2018; 1862:403-413. [DOI: 10.1016/j.bbagen.2017.11.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 11/10/2017] [Accepted: 11/13/2017] [Indexed: 01/07/2023]
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Pinhel MADS, Noronha NY, Nicoletti CF, de Oliveira BAP, Cortes-Oliveira C, Pinhanelli VC, Salgado Junior W, Machry AJ, da Silva Junior WA, Souza DRS, Marchini JS, Nonino CB. Changes in Global Transcriptional Profiling of Women Following Obesity Surgery Bypass. Obes Surg 2018; 28:176-186. [PMID: 28735374 DOI: 10.1007/s11695-017-2828-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Differential gene expression in peripheral blood mononuclear cells (PBMCs) after Roux-en-Y gastric bypass (RYGB) is poorly characterized. Markers of these processes may provide a deeper understanding of the mechanisms that underlie these events. The main goal of this study was to identify changes in PBMC gene expression in women with obesity before and 6 months after RYGB-induced weight loss. METHODS The ribonucleic acid (RNA) of PBMCs from 13 obese women was analyzed before and 6 months after RYGB; the RNA of PBMCs from nine healthy women served as control. The gene expression levels were determined by microarray analysis. Significant differences in gene expression were validated by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS Microarray analysis for comparison of the pre- and postoperative periods showed that 1366 genes were differentially expressed genes (DEGs). The main pathways were related to gene transcription; lipid, energy, and glycide metabolism; inflammatory and immunological response; cell differentiation; oxidative stress regulation; response to endogenous and exogenous stimuli; substrate oxidation; mTOR signaling pathway; interferon signaling; mitogen-activated protein kinases (MAPK), cAMP response element binding protein (CREB1), heat shock factor 1 (HSF1), and sterol regulatory element binding protein 1c (SREBP-1c) gene expression; adipocyte differentiation; and methylation. CONCLUSIONS Six months after bariatric surgery and significant weight loss, many molecular pathways involved in obesity and metabolic diseases change. These findings are an important tool to identify potential targets for therapeutic intervention and clinical practice of nutritional genomics in obesity.
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Affiliation(s)
- Marcela Augusta de Souza Pinhel
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Natalia Yumi Noronha
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Carolina Ferreira Nicoletti
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Bruno Affonso Parente de Oliveira
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Cristiana Cortes-Oliveira
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Vitor Caressato Pinhanelli
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Wilson Salgado Junior
- Department of Surgery and Anatomy, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Ribeirao Preto, SP, Brazil
| | - Ana Julia Machry
- Department of Genetics, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Ribeirao Preto, SP, Brazil
| | - Wilson Araújo da Silva Junior
- Department of Genetics, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Ribeirao Preto, SP, Brazil
| | - Dorotéia Rossi Silva Souza
- Department of Molecular Biology, São Jose do Rio Preto Medical School, São Jose do Rio Preto, SP, Brazil
| | - Júlio Sérgio Marchini
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil
| | - Carla Barbosa Nonino
- Department of Internal Medicine, Laboratory of Nutrigenomic Studies, Ribeirao Preto Medical School, FMRP, University of Sao Paulo, USP, Av Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, 14049-900, Brazil.
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Pastel E, Price E, Sjöholm K, McCulloch LJ, Rittig N, Liversedge N, Knight B, Møller N, Svensson PA, Kos K. Lysyl oxidase and adipose tissue dysfunction. Metabolism 2018; 78:118-127. [PMID: 29051043 DOI: 10.1016/j.metabol.2017.10.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 09/01/2017] [Accepted: 10/05/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND/OBJECTIVES Lysyl oxidase (LOX) is an enzyme crucial for collagen fibre crosslinking and thus for fibrosis development. Fibrosis is characterised by a surplus of collagen fibre accumulation and is amongst others also a feature of obesity-associated dysfunctional adipose tissue (AT) which has been linked with type 2 diabetes. We hypothesised that in type 2 diabetes and obesity LOX expression and activity will be increased as a consequence of worsening AT dysfunction. This study aimed to provide a comprehensive characterisation of LOX in human AT. METHODS LOX mRNA expression was analysed in omental and abdominal subcutaneous AT obtained during elective surgery from subjects with a wide range of BMI, with and without diabetes. In addition, LOX expression was studied in subcutaneous AT before and 9.5months after bariatric surgery. To study the mechanism of LOX changes, its expression and activity were assessed after either hypoxia, recombinant human leptin or glucose treatment of AT explants. In addition, LOX response to acute inflammation was tested after stimulation by a single injection of lipopolysaccharide versus saline solution (control) in healthy men, in vivo. Quantity of mRNA was measured by RT-qPCR. RESULTS LOX expression was higher in obesity and correlated with BMI whilst, in vitro, leptin at high concentrations, as a potential feedback mechanism, suppressed its expression. Neither diabetes status, nor hyperglycaemia affected LOX. Hypoxia and lipopolysaccharide-induced acute inflammation increased LOX AT expression, latter was independent of macrophage infiltration. CONCLUSIONS Whilst LOX may not be affected by obesity-associated complications such as diabetes, our results confirm that LOX is increased by hypoxia and inflammation as underlying mechanism for its upregulation in adipose tissue with obesity.
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Affiliation(s)
- Emilie Pastel
- Diabetes and Obesity Research Group, University of Exeter Medical School, Exeter, UK
| | - Emily Price
- Diabetes and Obesity Research Group, University of Exeter Medical School, Exeter, UK
| | - Kajsa Sjöholm
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Laura J McCulloch
- Diabetes and Obesity Research Group, University of Exeter Medical School, Exeter, UK
| | - Nikolaj Rittig
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Bridget Knight
- RD&E NHS Foundation Trust, Exeter, UK; NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK
| | - Niels Møller
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
| | - Per-Arne Svensson
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Katarina Kos
- Diabetes and Obesity Research Group, University of Exeter Medical School, Exeter, UK.
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Camastra S, Vitali A, Anselmino M, Gastaldelli A, Bellini R, Berta R, Severi I, Baldi S, Astiarraga B, Barbatelli G, Cinti S, Ferrannini E. Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery. Sci Rep 2017; 7:9007. [PMID: 28827671 PMCID: PMC5566429 DOI: 10.1038/s41598-017-08444-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 07/12/2017] [Indexed: 12/25/2022] Open
Abstract
Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat. We related the histology of subcutaneous (SAT), visceral fat (VAT), and skeletal muscle to the metabolic abnormalities, and tested their mutual changes after bariatric surgery in type 2 diabetic (T2D) and weight-matched non-diabetic (ND) patients. We measured IR (insulin clamp), lipolysis (2H5-glycerol infusion), ß-cell glucose-sensitivity (ß-GS, mathematical modeling), and VAT, SAT, and rectus abdominis histology (light and electron microscopy). Presurgery, SAT and VAT showed signs of fibrosis/necrosis, small mitochondria, free interstitial lipids, thickened capillary basement membrane. Compared to ND, T2D had impaired ß-GS, intracapillary neutrophils and higher intramyocellular fat, adipocyte area in VAT, crown-like structures (CLS) in VAT and SAT with rare structures (cyst-like) ~10-fold larger than CLS. Fat expansion was associated with enhanced lipolysis and IR. VAT histology and intramyocellular fat were related to impaired ß-GS. Postsurgery, IR and lipolysis improved in all, ß-GS improved in T2D. Muscle fat infiltration was reduced, adipocytes were smaller and richer in mitochondria, and CLS density in SAT was reduced. In conclusion, IR improves proportionally to weight loss but remains subnormal, whilst SAT and muscle changes disappear. In T2D postsurgery, some VAT pathology persists and beta-cell dysfunction improves but is not normalized.
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Affiliation(s)
- Stefania Camastra
- Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Alessandra Vitali
- Department of Experimental and Clinical Medicine-Center of Obesity, University of Ancona, Ancona, Italy
| | | | | | | | - Rossana Berta
- Bariatric Surgery Unit, Santa Chiara Hospital, Pisa, Italy
| | - Ilenia Severi
- Department of Experimental and Clinical Medicine-Center of Obesity, University of Ancona, Ancona, Italy
| | - Simona Baldi
- Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy
| | - Brenno Astiarraga
- Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giorgio Barbatelli
- Department of Experimental and Clinical Medicine-Center of Obesity, University of Ancona, Ancona, Italy
| | - Saverio Cinti
- Department of Experimental and Clinical Medicine-Center of Obesity, University of Ancona, Ancona, Italy
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Abstract
Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole-body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity-related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood. In this review, we discuss the current understanding of conditions of adipose tissue wasting and review microenvironmental determinants of adipocyte (dys)function in related pathophysiologies.
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Affiliation(s)
- Alexandros Vegiopoulos
- Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany
| | - Maria Rohm
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Stephan Herzig
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Joint Heidelberg-IDC Translational Diabetes Program Inner Medicine I, Neuherberg, Germany
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Chabot K, Gauthier MS, Garneau P, Rabasa-Lhoret R. Evolution of subcutaneous adipose tissue fibrosis after bariatric surgery. DIABETES & METABOLISM 2017; 43:125-133. [DOI: 10.1016/j.diabet.2016.10.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/15/2016] [Accepted: 10/16/2016] [Indexed: 10/20/2022]
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Zamarron BF, Mergian TA, Cho KW, Martinez-Santibanez G, Luan D, Singer K, DelProposto JL, Geletka LM, Muir LA, Lumeng CN. Macrophage Proliferation Sustains Adipose Tissue Inflammation in Formerly Obese Mice. Diabetes 2017; 66:392-406. [PMID: 28108608 PMCID: PMC5248991 DOI: 10.2337/db16-0500] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 10/29/2016] [Indexed: 12/12/2022]
Abstract
Obesity causes dramatic proinflammatory changes in the adipose tissue immune environment, but relatively little is known regarding how this inflammation responds to weight loss (WL). To understand the mechanisms by which meta-inflammation resolves during WL, we examined adipose tissue leukocytes in mice after withdrawal of a high-fat diet. After 8 weeks of WL, mice achieved similar weights and glucose tolerance values as age-matched lean controls but showed abnormal insulin tolerance. Despite fat mass normalization, total and CD11c+ adipose tissue macrophage (ATM) content remained elevated in WL mice for up to 6 months and was associated with persistent fibrosis in adipose tissue. ATMs in formerly obese mice demonstrated a proinflammatory profile, including elevated expression of interferon-γ, tumor necrosis factor-α, and interleukin-1β. T-cell-deficient Rag1-/- mice showed a degree of ATM persistence similar to that in WT mice, but with reduced inflammatory gene expression. ATM proliferation was identified as the predominant mechanism by which ATMs are retained in adipose tissue with WL. Our study suggests that WL does not completely resolve obesity-induced ATM activation, which may contribute to the persistent adipose tissue damage and reduced insulin sensitivity observed in formerly obese mice.
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Affiliation(s)
- Brian F Zamarron
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI
| | - Taleen A Mergian
- College of Literature Sciences and Arts, University of Michigan, Ann Arbor, MI
| | - Kae Won Cho
- Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do, Korea
| | | | - Danny Luan
- College of Literature Sciences and Arts, University of Michigan, Ann Arbor, MI
| | - Kanakadurga Singer
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI
| | - Jennifer L DelProposto
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI
| | - Lynn M Geletka
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI
| | - Lindsey A Muir
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI
| | - Carey N Lumeng
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI
- Department of Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI
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Singer K, Lumeng CN. The initiation of metabolic inflammation in childhood obesity. J Clin Invest 2017; 127:65-73. [PMID: 28045405 DOI: 10.1172/jci88882] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
An understanding of the events that initiate metabolic inflammation (metainflammation) can support the identification of targets for preventing metabolic disease and its negative effects on health. There is ample evidence demonstrating that the initiating events in obesity-induced inflammation start early in childhood. This has significant implications on our understanding of how early life events in childhood influence adult disease. In this Review we frame the initiating events of metainflammation in the context of child development and discuss what this reveals about the mechanisms by which this unique form of chronic inflammation is initiated and sustained into adulthood.
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Frikke-Schmidt H, O'Rourke RW, Lumeng CN, Sandoval DA, Seeley RJ. Does bariatric surgery improve adipose tissue function? Obes Rev 2016; 17:795-809. [PMID: 27272117 PMCID: PMC5328428 DOI: 10.1111/obr.12429] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 03/25/2016] [Accepted: 04/20/2016] [Indexed: 12/19/2022]
Abstract
Bariatric surgery is currently the most effective treatment for obesity. Not only do these types of surgeries produce significant weight loss but also they improve insulin sensitivity and whole body metabolic function. The aim of this review is to explore how altered physiology of adipose tissue may contribute to the potent metabolic effects of some of these procedures. This includes specific effects on various fat depots, the function of individual adipocytes and the interaction between adipose tissue and other key metabolic tissues. Besides a dramatic loss of fat mass, bariatric surgery shifts the distribution of fat from visceral to the subcutaneous compartment favoring metabolic improvement. The sensitivity towards lipolysis controlled by insulin and catecholamines is improved, adipokine secretion is altered and local adipose inflammation as well as systemic inflammatory markers decreases. Some of these changes have been shown to be weight loss independent, and novel hypothesis for these effects includes include changes in bile acid metabolism, gut microbiota and central regulation of metabolism. In conclusion bariatric surgery is capable of improving aspects of adipose tissue function and do so in some cases in ways that are not entirely explained by the potent effect of surgery. © 2016 World Obesity.
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Affiliation(s)
| | - R W O'Rourke
- Department of Surgery, University of Michigan, Ann Arbor, USA
| | - C N Lumeng
- Department of Pediatrics, University of Michigan, Ann Arbor, USA
| | - D A Sandoval
- Department of Surgery, University of Michigan, Ann Arbor, USA
| | - R J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, USA
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Szrok S, Stelmanska E, Turyn J, Bielicka-Gieldon A, Sledzinski T, Swierczynski J. Metallothioneins 1 and 2, but not 3, are regulated by nutritional status in rat white adipose tissue. GENES AND NUTRITION 2016; 11:18. [PMID: 27551319 PMCID: PMC4968437 DOI: 10.1186/s12263-016-0533-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/10/2016] [Indexed: 11/23/2022]
Abstract
Background Cumulating evidence underlines the role of adipose tissue metallothionein (MT) in the development of obesity and type 2 diabetes. Fasting/refeeding was shown to affect MT gene expression in the rodent liver. The influence of nutritional status on MT gene expression in white adipose tissue (WAT) is inconclusive. The aim of this study was to verify if fasting and fasting/refeeding may influence expression of MT genes in WAT of rats. Results Fasting resulted in a significant increase in MT1 and MT2 gene expressions in retroperitoneal, epididymal, and inguinal WAT of rats, and this effect was reversed by refeeding. Altered expressions of MT1 and MT2 genes in all main fat depots were reflected by changes in serum MT1 and MT2 levels. MT1 and MT2 messenger RNA (mRNA) levels in WAT correlated inversely with serum insulin concentration. Changes in MT1 and MT2 mRNA levels were apparently not related to total zinc concentrations and MTF1 and Zn transporter mRNA levels in WAT. Fasting or fasting/refeeding exerted no effect on the expression of MT3 gene in WAT. Addition of insulin to isolated adipocytes resulted in a significant decrease in MT1 and MT2 gene expressions. In contrast, forskolin or dibutyryl-cAMP (dB-cAMP) enhanced the expressions of MT1 and MT2 genes in isolated adipocytes. Insulin partially reversed the effect of dB-cAMP on MT1 and MT2 gene expressions. Conclusions This study showed that the expressions of MT1 and MT2 genes in WAT are regulated by nutritional status, and the regulation may be independent of total zinc concentration. Electronic supplementary material The online version of this article (doi:10.1186/s12263-016-0533-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sylwia Szrok
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | - Ewa Stelmanska
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | - Jacek Turyn
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | | | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | - Julian Swierczynski
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
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Seo BR, Bhardwaj P, Choi S, Gonzalez J, Andresen Eguiluz RC, Wang K, Mohanan S, Morris PG, Du B, Zhou XK, Vahdat LT, Verma A, Elemento O, Hudis CA, Williams RM, Gourdon D, Dannenberg AJ, Fischbach C. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 2016; 7:301ra130. [PMID: 26290412 DOI: 10.1126/scitranslmed.3010467] [Citation(s) in RCA: 246] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
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Affiliation(s)
- Bo Ri Seo
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Priya Bhardwaj
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Siyoung Choi
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Jacqueline Gonzalez
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | | | - Karin Wang
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Sunish Mohanan
- Department of Biological and Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Patrick G Morris
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Baoheng Du
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Xi K Zhou
- Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY 10065, USA
| | - Linda T Vahdat
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Akanksha Verma
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Clifford A Hudis
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rebecca M Williams
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Delphine Gourdon
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Andrew J Dannenberg
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Claudia Fischbach
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY 14853, USA.
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Effect of Roux-en-Y gastric bypass-induced weight loss on the transcriptomic profiling of subcutaneous adipose tissue. Surg Obes Relat Dis 2015; 12:257-63. [PMID: 26615868 DOI: 10.1016/j.soard.2015.07.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 07/03/2015] [Accepted: 07/07/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND The changes in the transcriptomic profiling of subcutaneous adipose tissue (SAT) when weight loss stabilizes after a Roux-en-Y gastric bypass (RYGB) are still largely unknown. OBJECTIVES To investigate the changes produced in SAT gene expression of morbidly obese women when their weight loss stabilizes 2 years after RYGB. SETTING University hospital. METHODS SAT biopsies of the periumbilical area were taken before and 2 years after RYGB. Gene expression levels were assessed by microarray analysis and significant differences in gene expression were validated by real-time quantitative polymerase chain reaction. The findings were also confirmed in an independent population of morbidly obese women. RESULTS Microarray analysis revealed that the overexpressed differentially expressed genes have a prominent role in the pathways involved in biosynthetic processes, especially lipid or carboxylic ones (stearoyl-Coenzyme A desaturase-1, fatty acid desaturase-1, fatty acid elongase-6, ATP citrate lyase, fatty acid synthase, lipin-1, monoacylglycerol O-acyltransferase, patatin-like phospholipase domain containing-3, phosphate cytidylyltransferase-2, cholesteryl ester transfer protein, transmembrane 7 superfamily member 2, pyruvate carboxylase, and glycogen synthase 2). Most of the underexpressed differentially expressed genes are related with immune system and inflammation processes (immune responses, response to stress, cell death, regulation of biological quality, immune effector process, the response to endogenous stimulus, and the response to other types of stimulus). CONCLUSION An improvement of the SAT inflammatory and immune profile and an induction of genes involved in the regulation of lipid metabolism are shown when weight loss stabilizes 2 years after RYGB. Most of the genes shown are clearly linked to obesity and other metabolic disorders.
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Buechler C, Krautbauer S, Eisinger K. Adipose tissue fibrosis. World J Diabetes 2015; 6:548-553. [PMID: 25987952 PMCID: PMC4434075 DOI: 10.4239/wjd.v6.i4.548] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 01/12/2015] [Accepted: 02/11/2015] [Indexed: 02/05/2023] Open
Abstract
The increasing prevalence of obesity causes a major interest in white adipose tissue biology. Adipose tissue cells are surrounded by extracellular matrix proteins whose composition and remodeling is of crucial importance for cell function. The expansion of adipose tissue in obesity is linked to an inappropriate supply with oxygen and hypoxia development. Subsequent activation of hypoxia inducible factor 1 (HIF-1) inhibits preadipocyte differentiation and initiates adipose tissue fibrosis. Thereby adipose tissue growth is limited and excess triglycerides are stored in ectopic tissues. Stressed adipocytes and hypoxia contribute to immune cell immigration and activation which further aggravates adipose tissue fibrosis. There is substantial evidence that adipose tissue fibrosis is linked to metabolic dysfunction, both in rodent models and in the clinical setting. Peroxisome proliferator activated receptor gamma agonists and adiponectin both reduce adipose tissue fibrosis, inflammation and insulin resistance. Current knowledge suggests that antifibrotic drugs, increasing adipose tissue oxygen supply or HIF-1 antagonists will improve adipose tissue function and thereby ameliorate metabolic diseases.
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Silva KR, Liechocki S, Carneiro JR, Claudio-da-Silva C, Maya-Monteiro CM, Borojevic R, Baptista LS. Stromal-vascular fraction content and adipose stem cell behavior are altered in morbid obese and post bariatric surgery ex-obese women. Stem Cell Res Ther 2015; 6:72. [PMID: 25884374 PMCID: PMC4435525 DOI: 10.1186/s13287-015-0029-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 01/29/2015] [Accepted: 03/02/2015] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Subcutaneous adipose tissue is an interesting source of autologous stem cells with a fundamental role in the pathophysiology of obesity, metabolic syndromes and insulin resistance. We hypothesize that obesity could alter the stromal-vascular fraction (SVF) and adipose stem cell (ASCs) functions, which could compromise its regenerative behavior. Furthermore, we aimed to evaluate whether ASCs derived from post bariatric surgery ex-obese women maintain their functions in a similar fashion as do those from individuals who have never been obese. METHODS The SVF of subcutaneous adipose tissue from control (n = 6, body mass index - BMI - 27.5 ± 0.5 kg/m(2)), obese (n = 12, BMI 46.2 ± 5.1 kg/m(2)) and post bariatric surgery ex-obese (n = 7, initial BMI 47.8 ± 1.3 kg/m(2); final BMI 28.1 ± 1.1 kg/m(2)) women were isolated and evaluated by flow cytometry. ASCs were tested for lipid accumulation by perilipin, adipose differentiation-related protein (ADRP) and Oil Red O staining after adipogenic stimulus. The cytokines secreted by the ASCs and after lipid accumulation induction were also evaluated. RESULTS The subcutaneous adipose tissue of obese and post bariatric surgery ex-obese women was enriched in pericytes (p = 0.0345). The number of supra-adventitial cells was not altered in the obese patients, but it was highly enriched in the post bariatric surgery ex-obese women (p = 0.0099). The ASCs of the post bariatric surgery ex-obese patients secreted more MCP-1 (monocyte chemoattractant protein-1; p = 0.0078). After lipid accumulation induction, the ASCs of the patients in all groups secreted less IL-6 than the ASCs with no adipogenic stimulus (p < 0.0001). Obese ASCs with lipid accumulation secreted the highest amount of IL-6 (p < 0.001) whereas the ASCs from the controls secreted the highest amount of adiponectin (p < 0.0001). The ASCs from the post bariatric surgery ex-obese patients showed the highest levels of lipid accumulation whereas those from the obese women had the lowest levels (p < 0.0001). CONCLUSIONS SVF content and ASC behavior are altered in the subcutaneous adipose tissue of morbid obese women; these changes are not completely restored after bariatric surgery-induced weight loss. The cellular alterations described in this study could affect the regenerative effects of adipose stem cells. Further investigations are required to avoid jeopardizing the development of autologous stem cell-based therapies.
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Affiliation(s)
- Karina R Silva
- Programa de Pós-graduação em Clínica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil. .,Núcleo Multidisciplinar de Pesquisa UFRJ - Xerém em Biologia (Numpex-Bio), Universidade Federal do Rio de Janeiro, Polo Xerém, Duque de Caxias, RJ 25245-390, Brazil. .,Programa de Bioengenharia, Diretoria de Programas, Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Duque de Caxias, RJ 25250-020, Brazil.
| | - Sally Liechocki
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ 21.040-900, Brazil.
| | - João R Carneiro
- Departamento de Nutrologia do Hospital Universitário Clementino Fraga Filho, Universidade Fereal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil.
| | - Cesar Claudio-da-Silva
- Serviço de Cirurgia Plástica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil.
| | - Clarissa M Maya-Monteiro
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ 21.040-900, Brazil.
| | - Radovan Borojevic
- Programa de Pós-graduação em Clínica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil. .,Programa de Bioengenharia, Diretoria de Programas, Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Duque de Caxias, RJ 25250-020, Brazil.
| | - Leandra S Baptista
- Programa de Pós-graduação em Clínica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil. .,Núcleo Multidisciplinar de Pesquisa UFRJ - Xerém em Biologia (Numpex-Bio), Universidade Federal do Rio de Janeiro, Polo Xerém, Duque de Caxias, RJ 25245-390, Brazil. .,Programa de Bioengenharia, Diretoria de Programas, Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Duque de Caxias, RJ 25250-020, Brazil.
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Singer K, DelProposto J, Morris DL, Zamarron B, Mergian T, Maley N, Cho KW, Geletka L, Subbaiah P, Muir L, Martinez-Santibanez G, Lumeng CNK. Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells. Mol Metab 2014; 3:664-75. [PMID: 25161889 PMCID: PMC4142398 DOI: 10.1016/j.molmet.2014.06.005] [Citation(s) in RCA: 183] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 06/25/2014] [Accepted: 06/30/2014] [Indexed: 12/17/2022] Open
Abstract
Obesity is associated with an activated macrophage phenotype in multiple tissues that contributes to tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c+ adipose tissue macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c+ adipose tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to adipose tissue inflammation.
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Affiliation(s)
- Kanakadurga Singer
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jennifer DelProposto
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - David Lee Morris
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Brian Zamarron
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Taleen Mergian
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nidhi Maley
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kae Won Cho
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25 Bongjeong-ro Dongnam-gu, Cheonan-si, Chungcheongnam-do 330-930, South Korea
| | - Lynn Geletka
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Perla Subbaiah
- Department of Mathematics and Statistics, Oakland University, Rochester, MI, USA
| | - Lindsey Muir
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gabriel Martinez-Santibanez
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Carey Nien-Kai Lumeng
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
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Abstract
Fibrosis is increasingly appreciated as a major player in adipose tissue dysfunction. In rapidly expanding adipose tissue, pervasive hypoxia leads to an induction of HIF1α that in turn leads to a potent profibrotic transcriptional program. The pathophysiological impact of adipose tissue fibrosis is likely to play an equally important role on systemic metabolic alterations as fibrotic conditions play in the liver, heart, and kidney. Here, we discuss recent advances in our understanding of the genesis, modulation, and systemic impact of excessive extracellular matrix (ECM) accumulation in adipose tissue of both rodents and humans and the ensuing impact on metabolic dysfunction.
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Affiliation(s)
- Kai Sun
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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