Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Model
2.2. Histological Analysis of Fat Cell Size
2.3. Quantification of Metformin in Serum by Mass Spectrometry
2.4. Protein Precipitation, Digestion and StageTip Purification
2.5. Proteomic Screen by Mass Spectrometry and Further Data Analysis
2.6. Statistical Analyses
3. Results
3.1. Metformin Serum Levels
3.2. Impact on Body and pgWAT Weight
3.3. Metformin Treatment Appears to Reduce Fat Cell Size in pgWAT of Obese Dams
3.4. Substantial and Differing Effects on pgWAT Proteome by HFD and Metformin Treatment
3.5. HFD Feeding Alters the Expression of 196 Proteins in pgWAT Proteome of Pregnant Mice
3.6. Metformin Treatment Alters the Expression of 103 Proteins in pgWAT Proteome of Obese Pregnant Mice
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Apoa4 | Apolipoprotein A4 |
CECAD | Cluster of Excellence-Cellular Stress Responses in Aging-Associated Diseases |
Cyp2s1 | Cytochrome P450 2S1 |
G | Gestational day |
Gapdh | Glyceraldehyde-3-phosphate dehydrogenase |
HFD | High-fat diet |
HFD + MF | High-fat diet plus metformin treatment |
LANUV NRW | State Agency for Nature, Environment and Consumer Protection North Rhine-Westphalia |
LC-MS | Liquid chromatography-mass spectrometry |
Lrg1 | Leucine-rich HEV glycoprotein |
Mlycd | Malonyl-CoA decarboxylase |
Opa3 | Optic atrophy 3 protein homolog |
Pdk2 | Pyruvate dehydrogenase kinase isoform 2 |
pgWAT | Perigonadal white adipose tissue |
SD | Standard diet |
Selenbp1 | Selenium-binding protein 1 |
Serpina1b | Alpha-1 antitrypsin 1-2 |
Serpina1c | Alpha-1 antitrypsin 1-3 |
WAT | White adipose tissue |
References
- World Health Organization. Fact Sheet—Obesity and Overweight. Available online: https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight (accessed on 10 November 2021).
- Lisonkova, S.; Muraca, G.M.; Potts, J.; Liauw, J.; Chan, W.S.; Skoll, A.; Lim, K.I. Association Between Prepregnancy Body Mass Index and Severe Maternal Morbidity. JAMA 2017, 318, 1777–1786. [Google Scholar] [CrossRef] [PubMed]
- Devlieger, R.; Benhalima, K.; Damm, P.; Van Assche, A.; Mathieu, C.; Mahmood, T.; Dunne, F.; Bogaerts, A. Maternal obesity in Europe: Where do we stand and how to move forward? Eur. J. Obs. Gynecol. Reprod. Biol. 2016, 201, 203–208. [Google Scholar] [CrossRef] [PubMed]
- Bogaerts, A.; Van den Bergh, B.; Nuyts, E.; Martens, E.; Witters, I.; Devlieger, R. Socio-demographic and obstetrical correlates of pre-pregnancy body mass index and gestational weight gain. Clin. Obes. 2012, 2, 150–159. [Google Scholar] [CrossRef] [PubMed]
- Bodnar, L.M.; Ness, R.B.; Markovic, N.; Roberts, J.M. The risk of preeclampsia rises with increasing prepregnancy body mass index. Ann. Epidemiol. 2005, 15, 475–482. [Google Scholar] [CrossRef] [PubMed]
- Arendas, K.; Qiu, Q.; Gruslin, A. Obesity in pregnancy: Pre-conceptional to postpartum consequences. J. Obs. Gynaecol. Can. 2008, 30, 477–488. [Google Scholar] [CrossRef]
- O’Reilly, J.R.; Reynolds, R.M. The risk of maternal obesity to the long-term health of the offspring. Clin. Endocrinol. 2013, 78, 9–16. [Google Scholar] [CrossRef]
- Luo, L.; Liu, M. Adipose tissue in control of metabolism. J. Endocrinol. 2016, 231, R77–R99. [Google Scholar] [CrossRef] [Green Version]
- Kershaw, E.E.; Flier, J.S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 2004, 89, 2548–2556. [Google Scholar] [CrossRef]
- Fasshauer, M.; Blüher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 2015, 36, 461–470. [Google Scholar] [CrossRef]
- Fernandez-Sanchez, A.; Madrigal-Santillan, E.; Bautista, M.; Esquivel-Soto, J.; Morales-Gonzalez, A.; Esquivel-Chirino, C.; Durante-Montiel, I.; Sanchez-Rivera, G.; Valadez-Vega, C.; Morales-Gonzalez, J.A. Inflammation, oxidative stress, and obesity. Int. J. Mol. Sci. 2011, 12, 3117–3132. [Google Scholar] [CrossRef] [Green Version]
- Zatterale, F.; Longo, M.; Naderi, J.; Raciti, G.A.; Desiderio, A.; Miele, C.; Beguinot, F. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front. Physiol. 2019, 10, 1607. [Google Scholar] [CrossRef] [PubMed]
- Matsuda, M.; Shimomura, I. Roles of adiponectin and oxidative stress in obesity-associated metabolic and cardiovascular diseases. Rev. Endocr. Metab. Disord. 2014, 15, 1–10. [Google Scholar] [CrossRef]
- Ouchi, N.; Parker, J.L.; Lugus, J.J.; Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 2011, 11, 85–97. [Google Scholar] [CrossRef] [PubMed]
- Cotechini, T.; Graham, C.H. Aberrant maternal inflammation as a cause of pregnancy complications: A potential therapeutic target? Placenta 2015, 36, 960–966. [Google Scholar] [CrossRef]
- Brien, M.E.; Boufaied, I.; Bernard, N.; Forest, J.C.; Giguere, Y.; Girard, S. Specific inflammatory profile in each pregnancy complication: A comparative study. Am. J. Reprod. Immunol. 2020, 84, e13316. [Google Scholar] [CrossRef]
- Esteghamati, A.; Eskandari, D.; Mirmiranpour, H.; Noshad, S.; Mousavizadeh, M.; Hedayati, M.; Nakhjavani, M. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: A randomized clinical trial. Clin. Nutr. 2013, 32, 179–185. [Google Scholar] [CrossRef]
- Chakraborty, A.; Chowdhury, S.; Bhattacharyya, M. Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res. Clin. Pract. 2011, 93, 56–62. [Google Scholar] [CrossRef] [PubMed]
- Martin-Montalvo, A.; Mercken, E.M.; Mitchell, S.J.; Palacios, H.H.; Mote, P.L.; Scheibye-Knudsen, M.; Gomes, A.P.; Ward, T.M.; Minor, R.K.; Blouin, M.J.; et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 2013, 4, 2192. [Google Scholar] [CrossRef] [PubMed]
- Paneni, F.; Lüscher, T.F. Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes. Am. J. Cardiol. 2017, 120, S17–S27. [Google Scholar] [CrossRef] [Green Version]
- Nguyen, L.; Chan, S.Y.; Teo, A.K.K. Metformin from mother to unborn child—Are there unwarranted effects? EBioMedicine 2018, 35, 394–404. [Google Scholar] [CrossRef] [Green Version]
- Butalia, S.; Gutierrez, L.; Lodha, A.; Aitken, E.; Zakariasen, A.; Donovan, L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: A systematic review and meta-analysis. Diabet. Med. A J. Br. Diabet. Assoc. 2017, 34, 27–36. [Google Scholar] [CrossRef] [PubMed]
- Tertti, K.; Eskola, E.; Rönnemaa, T.; Haataja, L. Neurodevelopment of Two-Year-Old Children Exposed to Metformin and Insulin in Gestational Diabetes Mellitus. J. Dev. Behav. Pediatrics JDBP 2015, 36, 752–757. [Google Scholar] [CrossRef] [PubMed]
- Wouldes, T.A.; Battin, M.; Coat, S.; Rush, E.C.; Hague, W.M.; Rowan, J.A. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Arch. Dis. Child. Fetal Neonatal Ed. 2016, 101, F488–F493. [Google Scholar] [CrossRef] [PubMed]
- Rowan, J.A.; Rush, E.C.; Plank, L.D.; Lu, J.; Obolonkin, V.; Coat, S.; Hague, W.M. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res. Care 2018, 6, e000456. [Google Scholar] [CrossRef] [Green Version]
- Catalano, P.; deMouzon, S.H. Maternal obesity and metabolic risk to the offspring: Why lifestyle interventions may have not achieved the desired outcomes. Int. J. Obes. 2015, 39, 642–649. [Google Scholar] [CrossRef] [Green Version]
- Arner, P. Differences in lipolysis between human subcutaneous and omental adipose tissues. Ann. Med. 1995, 27, 435–438. [Google Scholar] [CrossRef]
- Bruun, J.M.; Lihn, A.S.; Pedersen, S.B.; Richelsen, B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): Implication of macrophages resident in the AT. J. Clin. Endocrinol. Metab. 2005, 90, 2282–2289. [Google Scholar] [CrossRef]
- Stolk, R.P.; Meijer, R.; Mali, W.P.; Grobbee, D.E.; van der Graaf, Y. Ultrasound measurements of intraabdominal fat estimate the metabolic syndrome better than do measurements of waist circumference. Am. J. Clin. Nutr. 2003, 77, 857–860. [Google Scholar] [CrossRef] [Green Version]
- Nusken, E.; Turnwald, E.M.; Fink, G.; Voggel, J.; Yosy, C.; Kretschmer, T.; Handwerk, M.; Wohlfarth, M.; Weber, L.T.; Hucklenbruch-Rother, E.; et al. Maternal High Fat Diet and in-Utero Metformin Exposure Significantly Impact upon the Fetal Renal Proteome of Male Mice. J. Clin. Med. 2019, 8, 663. [Google Scholar] [CrossRef] [Green Version]
- Appel, S.; Grothe, J.; Storck, S.; Janoschek, R.; Bae-Gartz, I.; Wohlfarth, M.; Handwerk, M.; Hucklenbruch-Rother, E.; Gellhaus, A.; Dotsch, J. A Potential Role for GSK3beta in Glucose-Driven Intrauterine Catch-Up Growth in Maternal Obesity. Endocrinology 2019, 160, 377–386. [Google Scholar] [CrossRef] [Green Version]
- Kretschmer, T.; Turnwald, E.M.; Janoschek, R.; Zentis, P.; Bae-Gartz, I.; Beers, T.; Handwerk, M.; Wohlfarth, M.; Ghilav, M.; Bloch, W.; et al. Maternal high fat diet-induced obesity affects trophoblast differentiation and placental function in mice. Biol. Reprod. 2020, 103, 1260–1274. [Google Scholar] [CrossRef] [PubMed]
- Bankhead, P.; Loughrey, M.B.; Fernández, J.A.; Dombrowski, Y.; McArt, D.G.; Dunne, P.D.; McQuaid, S.; Gray, R.T.; Murray, L.J.; Coleman, H.G.; et al. QuPath: Open source software for digital pathology image analysis. Sci. Rep. 2017, 7, 16878. [Google Scholar] [CrossRef] [Green Version]
- Schindelin, J.; Arganda-Carreras, I.; Frise, E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Preibisch, S.; Rueden, C.; Saalfeld, S.; Schmid, B.; et al. Fiji: An open-source platform for biological-image analysis. Nat. Methods 2012, 9, 676–682. [Google Scholar] [CrossRef] [Green Version]
- Galarraga, M.; Campión, J.; Muñoz-Barrutia, A.; Boqué, N.; Moreno, H.; Martínez, J.A.; Milagro, F.; Ortiz-de-Solórzano, C. Adiposoft: Automated software for the analysis of white adipose tissue cellularity in histological sections. J. Lipid Res. 2012, 53, 2791–2796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schommers, P.; Thurau, A.; Bultmann-Mellin, I.; Guschlbauer, M.; Klatt, A.R.; Rozman, J.; Klingenspor, M.; de Angelis, M.H.; Alber, J.; Gründemann, D.; et al. Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state. Mol. Metab. 2017, 6, 737–747. [Google Scholar] [CrossRef] [PubMed]
- Proteomics Core Facility Cologne. Proteomic Screen Protocols. Available online: http://proteomics.cecad-labs.uni-koeln.de/Protocols.955.0.html (accessed on 11 May 2021).
- MaxQuant, version 1.5.3.8; Max-Planck-Institute of Biochemistry: Planegg, Germany, 2008.
- Perseus, version 1.6.1.1; Max-Planck-Institute of Biochemistry: Planegg, Germany, 2012.
- Tusher, V.G.; Tibshirani, R.; Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 2001, 98, 5116–5121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pathan, M.; Keerthikumar, S.; Ang, C.S.; Gangoda, L.; Quek, C.Y.; Williamson, N.A.; Mouradov, D.; Sieber, O.M.; Simpson, R.J.; Salim, A.; et al. FunRich: An open access standalone functional enrichment and interaction network analysis tool. Proteomics 2015, 15, 2597–2601. [Google Scholar] [CrossRef]
- Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; et al. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019, 47, D607–D613. [Google Scholar] [CrossRef] [Green Version]
- UniProt Consortium. UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res. 2019, 47, D506–D515. [Google Scholar] [CrossRef] [Green Version]
- Kajbaf, F.; De Broe, M.E.; Lalau, J.D. Therapeutic Concentrations of Metformin: A Systematic Review. Clin. Pharmacokinet. 2016, 55, 439–459. [Google Scholar] [CrossRef]
- Liao, M.Z.; Flood Nichols, S.K.; Ahmed, M.; Clark, S.; Hankins, G.D.; Caritis, S.; Venkataramanan, R.; Haas, D.; Quinney, S.K.; Haneline, L.S.; et al. Effects of Pregnancy on the Pharmacokinetics of Metformin. Drug Metab. Dispos. Biol. Fate Chem. 2020, 48, 264–271. [Google Scholar] [CrossRef] [PubMed]
- Seifarth, C.; Schehler, B.; Schneider, H.J. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp. Clin. Endocrinol. Diabetes 2013, 121, 27–31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cedergren, M.I. Optimal gestational weight gain for body mass index categories. Obs. Gynecol. 2007, 110, 759–764. [Google Scholar] [CrossRef] [PubMed]
- Artal, R.; Lockwood, C.J.; Brown, H.L. Weight gain recommendations in pregnancy and the obesity epidemic. Obs. Gynecol. 2010, 115, 152–155. [Google Scholar] [CrossRef] [Green Version]
- Bogaerts, A.; Ameye, L.; Martens, E.; Devlieger, R. Weight loss in obese pregnant women and risk for adverse perinatal outcomes. Obs. Gynecol. 2015, 125, 566–575. [Google Scholar] [CrossRef] [PubMed]
- Catalano, P.M.; Mele, L.; Landon, M.B.; Ramin, S.M.; Reddy, U.M.; Casey, B.; Wapner, R.J.; Varner, M.W.; Rouse, D.J.; Thorp, J.M., Jr.; et al. Inadequate weight gain in overweight and obese pregnant women: What is the effect on fetal growth? Am. J. Obs. Gynecol 2014, 211, 137.e1–137.e7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kominiarek, M.A.; Peaceman, A.M. Gestational weight gain. Am. J. Obs. Gynecol. 2017, 217, 642–651. [Google Scholar] [CrossRef]
- Syngelaki, A.; Nicolaides, K.H.; Balani, J.; Hyer, S.; Akolekar, R.; Kotecha, R.; Pastides, A.; Shehata, H. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. New Engl. J. Med. 2016, 374, 434–443. [Google Scholar] [CrossRef]
- Virtanen, K.A.; Hällsten, K.; Parkkola, R.; Janatuinen, T.; Lönnqvist, F.; Viljanen, T.; Rönnemaa, T.; Knuuti, J.; Huupponen, R.; Lönnroth, P.; et al. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes 2003, 52, 283–290. [Google Scholar] [CrossRef] [Green Version]
- Tokubuchi, I.; Tajiri, Y.; Iwata, S.; Hara, K.; Wada, N.; Hashinaga, T.; Nakayama, H.; Mifune, H.; Yamada, K. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS ONE 2017, 12, e0171293. [Google Scholar] [CrossRef]
- Souza-Mello, V.; Gregório, B.M.; Cardoso-de-Lemos, F.S.; de Carvalho, L.; Aguila, M.B.; Mandarim-de-Lacerda, C.A. Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin. Sci. 2010, 119, 239–250. [Google Scholar] [CrossRef] [PubMed]
- Blüher, M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract. Res. Clin. Endocrinol. Metab. 2013, 27, 163–177. [Google Scholar] [CrossRef] [PubMed]
- Skurk, T.; Alberti-Huber, C.; Herder, C.; Hauner, H. Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 2007, 92, 1023–1033. [Google Scholar] [CrossRef] [PubMed]
- Tansey, J.T.; Sztalryd, C.; Gruia-Gray, J.; Roush, D.L.; Zee, J.V.; Gavrilova, O.; Reitman, M.L.; Deng, C.X.; Li, C.; Kimmel, A.R.; et al. Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl. Acad. Sci. USA 2001, 98, 6494–6499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martinez-Botas, J.; Anderson, J.B.; Tessier, D.; Lapillonne, A.; Chang, B.H.; Quast, M.J.; Gorenstein, D.; Chen, K.H.; Chan, L. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat. Genet. 2000, 26, 474–479. [Google Scholar] [CrossRef]
- Jones, J.E.C.; Rabhi, N.; Orofino, J.; Gamini, R.; Perissi, V.; Vernochet, C.; Farmer, S.R. The Adipocyte Acquires a Fibroblast-Like Transcriptional Signature in Response to a High Fat Diet. Sci. Rep. 2020, 10, 2380. [Google Scholar] [CrossRef]
- Schöttl, T.; Kappler, L.; Fromme, T.; Klingenspor, M. Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status. Mol. Metab. 2015, 4, 631–642. [Google Scholar] [CrossRef]
- Cummins, T.D.; Holden, C.R.; Sansbury, B.E.; Gibb, A.A.; Shah, J.; Zafar, N.; Tang, Y.; Hellmann, J.; Rai, S.N.; Spite, M.; et al. Metabolic remodeling of white adipose tissue in obesity. Am. J. Physiol. Endocrinol. Metab. 2014, 307, E262–E277. [Google Scholar] [CrossRef]
- Choi, M.S.; Kim, Y.J.; Kwon, E.Y.; Ryoo, J.Y.; Kim, S.R.; Jung, U.J. High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes. Br. J. Nutr. 2015, 113, 867–877. [Google Scholar] [CrossRef] [Green Version]
- Shaik, A.A.; Qiu, B.; Wee, S.; Choi, H.; Gunaratne, J.; Tergaonkar, V. Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet. Sci. Rep. 2016, 6, 25844. [Google Scholar] [CrossRef] [Green Version]
- Bouzakri, K.; Austin, R.; Rune, A.; Lassman, M.E.; Garcia-Roves, P.M.; Berger, J.P.; Krook, A.; Chibalin, A.V.; Zhang, B.B.; Zierath, J.R. Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes 2008, 57, 1508–1516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cadoudal, T.; Distel, E.; Durant, S.; Fouque, F.; Blouin, J.M.; Collinet, M.; Bortoli, S.; Forest, C.; Benelli, C. Pyruvate dehydrogenase kinase 4: Regulation by thiazolidinediones and implication in glyceroneogenesis in adipose tissue. Diabetes 2008, 57, 2272–2279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ralser, M.; Wamelink, M.M.; Kowald, A.; Gerisch, B.; Heeren, G.; Struys, E.A.; Klipp, E.; Jakobs, C.; Breitenbach, M.; Lehrach, H.; et al. Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J. Biol. 2007, 6, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bui, P.; Imaizumi, S.; Beedanagari, S.R.; Reddy, S.T.; Hankinson, O. Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids. Drug Metab. Dispos. Biol. Fate Chem. 2011, 39, 180–190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Janciauskiene, S.M.; Bals, R.; Koczulla, R.; Vogelmeier, C.; Köhnlein, T.; Welte, T. The discovery of α1-antitrypsin and its role in health and disease. Respir. Med. 2011, 105, 1129–1139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kalis, M.; Kumar, R.; Janciauskiene, S.; Salehi, A.; Cilio, C.M. α 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic β-cells. Islets 2010, 2, 185–189. [Google Scholar] [CrossRef] [Green Version]
- Sandström, C.S.; Ohlsson, B.; Melander, O.; Westin, U.; Mahadeva, R.; Janciauskiene, S. An association between Type 2 diabetes and alpha-antitrypsin deficiency. Diabet. Med. A J. Br. Diabet. Assoc. 2008, 25, 1370–1373. [Google Scholar] [CrossRef]
- Rachmiel, M.; Strauss, P.; Dror, N.; Benzaquen, H.; Horesh, O.; Tov, N.; Weintrob, N.; Landau, Z.; Ben-Ami, M.; Haim, A.; et al. Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus. Pediatric Diabetes 2016, 17, 351–359. [Google Scholar] [CrossRef]
- Weinberg, R.B.; Dantzker, C.; Patton, C.S. Sensitivity of serum apolipoprotein A-IV levels to changes in dietary fat content. Gastroenterology 1990, 98, 17–24. [Google Scholar] [CrossRef]
- Qu, J.; Ko, C.W.; Tso, P.; Bhargava, A. Apolipoprotein A-IV: A Multifunctional Protein Involved in Protection against Atherosclerosis and Diabetes. Cells 2019, 8, 319. [Google Scholar] [CrossRef] [Green Version]
- Yang, F.J.; Hsieh, C.Y.; Shu, K.H.; Chen, I.Y.; Pan, S.Y.; Chuang, Y.F.; Chiu, Y.L.; Yang, W.S. Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease. Sci. Rep. 2020, 10, 5988. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Steinbrenner, H.; Micoogullari, M.; Hoang, N.A.; Bergheim, I.; Klotz, L.O.; Sies, H. Selenium-binding protein 1 (SELENBP1) is a marker of mature adipocytes. Redox Biol. 2019, 20, 489–495. [Google Scholar] [CrossRef] [PubMed]
- Elhodaky, M.; Diamond, A.M. Selenium-Binding Protein 1 in Human Health and Disease. Int. J. Mol. Sci. 2018, 19, 3437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kühn, E.C.; Slagman, A.; Kühn-Heid, E.C.D.; Seelig, J.; Schwiebert, C.; Minich, W.B.; Stoppe, C.; Möckel, M.; Schomburg, L. Circulating levels of selenium-binding protein 1 (SELENBP1) are associated with risk for major adverse cardiac events and death. J. Trace Elem. Med. Biol. 2019, 52, 247–253. [Google Scholar] [CrossRef]
- Wells, T.; Davies, J.R.; Guschina, I.A.; Ball, D.J.; Davies, J.S.; Davies, V.J.; Evans, B.A.; Votruba, M. Opa3, a novel regulator of mitochondrial function, controls thermogenesis and abdominal fat mass in a mouse model for Costeff syndrome. Hum. Mol. Genet. 2012, 21, 4836–4844. [Google Scholar] [CrossRef] [Green Version]
- Hiraike, Y.; Waki, H.; Yu, J.; Nakamura, M.; Miyake, K.; Nagano, G.; Nakaki, R.; Suzuki, K.; Kobayashi, H.; Yamamoto, S.; et al. NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program. Nat. Cell Biol. 2017, 19, 1081–1092. [Google Scholar] [CrossRef] [Green Version]
- Kim, E.K.; Lee, S.H.; Jhun, J.Y.; Byun, J.K.; Jeong, J.H.; Lee, S.Y.; Kim, J.K.; Choi, J.Y.; Cho, M.L. Metformin Prevents Fatty Liver and Improves Balance of White/Brown Adipose in an Obesity Mouse Model by Inducing FGF21. Mediat. Inflamm. 2016, 2016, 5813030. [Google Scholar] [CrossRef]
- Brockman, D.; Chen, X. Proteomics in the characterization of adipose dysfunction in obesity. Adipocyte 2012, 1, 25–37. [Google Scholar] [CrossRef] [Green Version]
- Chusyd, D.E.; Wang, D.; Huffman, D.M.; Nagy, T.R. Relationships between Rodent White Adipose Fat Pads and Human White Adipose Fat Depots. Front. Nutr. 2016, 3, 10. [Google Scholar] [CrossRef] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Schmitz, K.; Turnwald, E.-M.; Kretschmer, T.; Janoschek, R.; Bae-Gartz, I.; Voßbrecher, K.; Kammerer, M.D.; Köninger, A.; Gellhaus, A.; Handwerk, M.; et al. Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice. Nutrients 2022, 14, 2288. https://doi.org/10.3390/nu14112288
Schmitz K, Turnwald E-M, Kretschmer T, Janoschek R, Bae-Gartz I, Voßbrecher K, Kammerer MD, Köninger A, Gellhaus A, Handwerk M, et al. Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice. Nutrients. 2022; 14(11):2288. https://doi.org/10.3390/nu14112288
Chicago/Turabian StyleSchmitz, Katrin, Eva-Maria Turnwald, Tobias Kretschmer, Ruth Janoschek, Inga Bae-Gartz, Kathrin Voßbrecher, Merlin D. Kammerer, Angela Köninger, Alexandra Gellhaus, Marion Handwerk, and et al. 2022. "Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice" Nutrients 14, no. 11: 2288. https://doi.org/10.3390/nu14112288
APA StyleSchmitz, K., Turnwald, E. -M., Kretschmer, T., Janoschek, R., Bae-Gartz, I., Voßbrecher, K., Kammerer, M. D., Köninger, A., Gellhaus, A., Handwerk, M., Wohlfarth, M., Gründemann, D., Hucklenbruch-Rother, E., Dötsch, J., & Appel, S. (2022). Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice. Nutrients, 14(11), 2288. https://doi.org/10.3390/nu14112288