Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2019

Open Access 01-12-2019 | Endometriosis | Research

Adipocyte alterations in endometriosis: reduced numbers of stem cells and microRNA induced alterations in adipocyte metabolic gene expression

Authors: Masoumeh Majidi Zolbin, Ramanaiah Mamillapalli, Sepide E. Nematian, Teddy G. Goetz, Hugh S. Taylor

Published in: Reproductive Biology and Endocrinology | Issue 1/2019

Login to get access

Abstract

Background

Endometriosis is an estrogen dependent, inflammatory disorder occurring in 5–10% of reproductive-aged women. Women with endometriosis have a lower body mass index (BMI) and decreased body fat compared to those without the disease, yet few studies have focused on the metabolic abnormalities in adipose tissue in women with endometriosis. Previously, we identified microRNAs that are differentially expressed in endometriosis and altered in the serum of women with the disease. Here we explore the effect of endometriosis on fat tissue and identified a role for endometriosis-related microRNAs in fat metabolism and a reduction in adipocyte stem cell number.

Methods

Primary adipocyte cells cultured from 20 patients with and without endometriosis were transfected with mimics and inhibitors of microRNAs 342-3p or Let 7b-5p to model the status of these microRNAs in endometriosis. RNA was extracted for gene expression analysis by qRT-PCR. PCNA expression was used as a marker of adipocyte proliferation. Endometriosis was induced experimentally in 9-week old female C57BL/6 mice and after 10 months fat tissue was harvested from both the subcutaneous (inguinal) and visceral (mesenteric) tissue. Adipose-derived mesenchymal stem cells in fat tissue were characterized in both endometriosis and non-endometriosis mice by FACS analysis.

Results

Gene expression analysis showed that endometriosis altered the expression of Cebpa, Cebpb, Ppar-γ, leptin, adiponectin, IL-6, and HSL, which are involved in driving brown adipocyte differentiation, appetite, insulin sensitivity and fat metabolism. Each gene was regulated by an alteration in microRNA expression known to occur in endometriosis. Analysis of the stem cell content of adipose tissue in a mouse model of endometriosis demonstrated a reduced number of adipocyte stem cells.

Conclusions

We demonstrate that microRNAs Let-7b and miR-342-3p affected metabolic gene expression significantly in adipocytes of women with endometriosis. Similarly, there is a reduction in the adipose stem cell population in a mouse model of endometriosis. Taken together these data suggest that endometriosis alters BMI in part through an effect on adipocytes and fat metabolism.
Literature
1.
2.
3.
Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin N Am. 2012;39:535–49.CrossRef
4.
Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin N Am. 1997;24:235–58.CrossRef
5.
6.
Li F, Alderman MH III, Tal A, Mamillapalli R, Coolidge A, Hufnagel D, Wang Z, Neisani E, Gidicsin S, Krikun G. Hematogenous dissemination of mesenchymal stem cells from endometriosis. Stem Cells. 2018;36:881–90.PubMedPubMedCentralCrossRef
7.
Ferrero S, Anserini P, Remorgida V, Ragni N. Body mass index in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2005;121:94–8.PubMedCrossRef
8.
Goetz LG, Mamillapalli R, Taylor HS. Low body mass index in endometriosis is promoted by hepatic metabolic gene dysregulation in mice. Biol Reprod. 2016;95:1–8.CrossRef
9.
Dutta M, Anitha M, Smith PB, Chiaro CR, Maan M, Chaudhury K, Patterson AD. Metabolomics reveals altered lipid metabolism in a mouse model of endometriosis. J Proteome Res. 2016;15:2626–33.PubMedCrossRef
10.
Squillace N, Bresciani E, Torsello A, Bandera A, Sabbatini F, Giovannetti C, Giunta G, Rovati L, Del Bene M, Locatelli V. Changes in subcutaneous adipose tissue microRNA expression in HIV-infected patients. J Antimicrob Chemother. 2014;69:3067–75.PubMedCrossRef
11.
Pachón-Peña G, Serena C, Ejarque M, Petriz J, Duran X, Oliva-Olivera W, Simó R, Tinahones FJ, Fernández-Veledo S, Vendrell J. Obesity determines the immunophenotypic profile and functional characteristics of human mesenchymal stem cells from adipose tissue. Stem Cells Transl Med. 2016;5:464–75.PubMedPubMedCentralCrossRef
12.
13.
Hufnagel D, Li F, Cosar E, Krikun G, Taylor HS. The role of stem cells in the etiology and pathophysiology of endometriosis. In: Seminars in reproductive medicine: Thieme Medical Publishers; 2015. p. 333–40.
14.
Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25:2082–6.PubMedCrossRef
15.
Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292:81–5.PubMedCrossRef
16.
17.
Sakr S, Naqvi H, Komm B, Taylor HS. Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas Bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology. 2014;155:1489–97.PubMedPubMedCentralCrossRef
18.
Aznaurova YB, Zhumataev MB, Roberts TK, Aliper AM, Zhavoronkov AA. Molecular aspects of development and regulation of endometriosis. Reprod Biol Endocrinol. 2014;12:50.PubMedPubMedCentralCrossRef
19.
20.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.PubMed
21.
22.
He T, Qi F, Jia L, Wang S, Song N, Guo L, Fu Y, Luo Y. MicroRNA-542-3p inhibits tumour angiogenesis by targeting Angiopoietin-2. J Pathol. 2014;232:499–508.PubMedCrossRef
23.
Ortega FJ, Moreno-Navarrete JM, Pardo G, Sabater M, Hummel M, Ferrer A, Rodriguez-Hermosa JI, Ruiz B, Ricart W, Peral B. MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation. PLoS One. 2010;5:e9022.PubMedPubMedCentralCrossRef
24.
Santamaria X, Taylor H. MicroRNA and gynecological reproductive diseases. Fertil Steril. 2014;101:1545–51.PubMedCrossRef
25.
26.
Teague EMCO, Hull ML. The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update. 2010;16:142–65.CrossRef
27.
Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B, Taylor HS. Serum microRNAs as diagnostic markers of endometriosis: a comprehensive array-based analysis. Fertil Steril. 2016;106:402–9.PubMedCrossRef
28.
Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, Flores I, Weidhaas JB, Taylor HS. A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med. 2012;4:206–17.PubMedPubMedCentralCrossRef
29.
Zhu H, Shyh-Chang N, Segre AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, et al. The Lin28/let-7 axis regulates glucose metabolism. Cell. 2011;147:81–94.PubMedPubMedCentralCrossRef
30.
Pérez LM, Bernal A, San Martín N, Lorenzo M, Fernández-Veledo S, Gálvez BG. Metabolic rescue of obese adipose-derived stem cells by Lin28/Let7 pathway. Diabetes. 2013;62:2368–79.PubMedPubMedCentralCrossRef
31.
Wang L, Xu L, Xu M, Liu G, Xing J, Sun C, Ding H. Obesity-associated MiR-342-3p promotes adipogenesis of mesenchymal stem cells by suppressing CtBP2 and releasing C/EBPα from CtBP2 binding. Cell Physiol Biochem. 2015;35:2285–98.PubMedCrossRef
32.
Li X, Chen Y-T, Josson S, Mukhopadhyay NK, Kim J, Freeman MR, Huang W-C. MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells. PLoS One. 2013;8:e70987.PubMedPubMedCentralCrossRef
33.
Arias N, Aguirre L, Fernández-Quintela A, González M, Lasa A, Miranda J, Macarulla M, Portillo M. MicroRNAs involved in the browning process of adipocytes. J Physiol Biochem. 2016;72:509–21.PubMedCrossRef
34.
35.
Naqvi H, Sakr S, Presti T, Krikun G, Komm B, Taylor HS. Treatment with bazedoxifene and conjugated estrogens results in regression of endometriosis in a murine model. Biol Reprod. 2014;90:121, 121–7.PubMedCrossRef
36.
Nematian SE, Mamillapalli R, Kadakia TS, Majidi Zolbin M, Moustafa S, Taylor HS. Systemic inflammation induced by microRNAs: endometriosis derived alterations in circulating microRNA 125b-5p and Let7b-5p regulate macrophage cytokine production. J Clin Endocrinol Metab. 2017.
37.
Bouayad D, Pederzoli-Ribeil M, Mocek J, Candalh C, Arlet JB, Hermine O, Reuter N, Davezac N, Witko-Sarsat V. Nuclear-to-cytoplasmic relocalization of the proliferating cell nuclear antigen (PCNA) during differentiation involves a chromosome region maintenance 1 (CRM1)-dependent export and is a prerequisite for PCNA antiapoptotic activity in mature neutrophils. J Biol Chem. 2012;287:33812–25.PubMedPubMedCentralCrossRef
38.
Naryzhny SN, Lee H. Proliferating cell nuclear antigen in the cytoplasm interacts with components of glycolysis and cancer. FEBS Lett. 2010;584:4292–8.PubMedCrossRef
39.
Ohayon D, De Chiara A, Chapuis N, Candalh C, Mocek J, Ribeil JA, Haddaoui L, Ifrah N, Hermine O, Bouillaud F, et al. Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia. Sci Rep. 2016;6:35561.PubMedPubMedCentralCrossRef
40.
Alderman MH III, Yoder N, Taylor HS. The systemic effects of endometriosis. In: Seminars in reproductive medicine: Thieme Medical Publishers; 2017. p. 263–70.
41.
Bjorkman S, Taylor HS. microRNAs in endometriosis: biological function and emerging biomarker candidates. Biol Reprod. 2019; PMD 30721951.
42.
43.
Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 2012;15:395–404.PubMedPubMedCentralCrossRef
44.
Akyurek N, Aycan Z, Cetinkaya S, Akyurek O, Yilmaz Agladioglu S, Ertan U. Peroxisome proliferator activated receptor (PPAR)-gamma concentrations in childhood obesity. Scand J Clin Lab Invest. 2013;73:355–60.PubMedCrossRef
45.
Holm C, Østerlund T, Laurell H, Contreras JA. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu Rev Nutr. 2000;20:365–93.PubMedCrossRef
46.
DePaoli AM. 20 YEARS OF LEPTIN: Leptin in common obesity and associated disorders of metabolism. J Endocrinol. 2014;223:T71–81.PubMedCrossRef
47.
Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999;401:73–6.PubMedCrossRef
48.
Turner RT, Dube M, Branscum AJ, Wong CP, Olson DA, Zhong X, Kweh MF, Larkin IV, Wronski TJ, Rosen CJ. Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss. J Endocrinol. 2015;227:129–41.PubMedPubMedCentralCrossRef
49.
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116:1784–92.PubMedPubMedCentralCrossRef
50.
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 2002;8:731–7.PubMedCrossRef
51.
Viengchareun S, Zennaro M-C, Tallec P-L, Lombes M. Brown adipocytes are novel sites of expression and regulation of adiponectin and resistin. FEBS Lett. 2002;532:345–50.PubMedCrossRef
52.
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.PubMedCrossRef
53.
Katsura A, Morishita A, Iwama H, Tani J, Sakamoto T, Tatsuta M, Toyota Y, Fujita K, Kato K, Maeda E. MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis. Int J Mol Med. 2015;35:877–84.PubMedPubMedCentralCrossRef
54.
Petersen E, Carey A, Sacchetti M, Steinberg G, Macaulay S, Febbraio M, Pedersen B. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab. 2005;288:E155–62.PubMedCrossRef
55.
Wolsk E, Mygind H, Grøndahl TS, Pedersen BK, van Hall G. IL-6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab. 2010;299:E832–40.PubMedCrossRef
56.
Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candalh C, Davezac N, Reuter N, Mouthon L, Hermine O, et al. Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. J Exp Med. 2010;207:2631–45.PubMedPubMedCentralCrossRef
57.
Li X-R, Chu H-J, Lv T, Wang L, Kong S-F, Dai S-Z. miR-342-3p suppresses proliferation, migration and invasion by targeting FOXM1 in human cervical cancer. FEBS Lett. 2014;588:3298–307.PubMedCrossRef
58.
Tao K, Yang J, Guo Z, Hu Y, Sheng H, Gao H, Yu H. Prognostic value of miR-221-3p, miR-342-3p and miR-491-5p expression in colon cancer. Am J Transl Res. 2014;6:391–401.PubMedPubMedCentral
59.
Büssing I, Slack FJ, Großhans H. Let-7 microRNAs in development, stem cells and cancer. Trends Mol Med. 2008;14:400–9.PubMedCrossRef
Metadata
Title
Adipocyte alterations in endometriosis: reduced numbers of stem cells and microRNA induced alterations in adipocyte metabolic gene expression
Authors
Masoumeh Majidi Zolbin
Ramanaiah Mamillapalli
Sepide E. Nematian
Teddy G. Goetz
Hugh S. Taylor
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Endometriosis
Published in
Reproductive Biology and Endocrinology / Issue 1/2019
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-019-0480-0

Other articles of this Issue 1/2019

Reproductive Biology and Endocrinology 1/2019 Go to the issue

Research

In vitro effect of nerve growth factor on the main traits of rabbit sperm

Research

Amniotic fluid antiphospholipid antibodies: potential role in antiphospholipid syndrome-independent aberrant implantation process

Research

Serum Antimüllerian hormone does not predict elevated progesterone levels among women who undergo controlled ovarian hyperstimulation for in vitro fertilization

Research

The risk of secondary sex ratio imbalance and increased monozygotic twinning after blastocyst transfer: data from the Japan Environment and Children’s Study

Research

Proteomic alterations underlie an association with teratozoospermia in obese mice sperm

Research

Impact of uteroplacental insufficiency on ovarian follicular pool in the rat