Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans
Abstract
:1. Introduction
2. Materials and Methods
2.1. Experimental Animals
2.2. Pancreas Immunohistochemistry
2.3. Pioglitazone-Treated Human Study Participants and RNA Isolation from Human Adipose Tissue
2.3.1. Study Participant Characteristics
2.3.2. Adipose Tissue Biopsies and RNA Isolation
2.4. Gene Expression Analysis
2.5. Serum Analyses
2.6. Statistical Analysis
3. Results
3.1. Pioglitazone (PIO) Lowers Blood Glucose in Obese Diabetic Mice
3.2. Four Weeks of PIO Therapy Increases Fat and Fluid Mass in db/db Mice
3.3. Pioglitazone Increases Respiratory Quotient (RQ) and Energy Expenditure (EE), but Does Not Alter Locomotor Activity or Food Intake
3.4. PIO Therapy Restores the Majority of Circulating Hormones in Obese Mice to Values Observed in Lean Controls
3.5. PIO Supplementation Alters Gene Expression Patterns in White Adipose Tissue from db/db Mice
3.6. Oral Pioglitazone Administration to Human Study Participants Alters White Adipose Tissue Gene Expression
3.7. db/db Mice on a PIO-Enhanced Diet Display Increased Expression of the Insulin Genes and Decreased Expression of the Aldh1a3 Gene
3.8. PIO-Supplemented Diet Restores Pancreatic Nkx6.1 Abundance and Decreases Abundance of the De-Differentiation Marker Aldh1a3 in db/db Mice
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Gonzalez-Muniesa, P.; Martinez-Gonzalez, M.A.; Hu, F.B.; Despres, J.P.; Matsuzawa, Y.; Loos, R.J.F.; Moreno, L.A.; Bray, G.A.; Martinez, J.A. Obesity. Nat. Rev. Dis. Primers 2017, 3, 17034. [Google Scholar] [CrossRef] [PubMed]
- DeFronzo, R.A.; Ferrannini, E.; Groop, L.; Henry, R.R.; Herman, W.H.; Holst, J.J.; Hu, F.B.; Kahn, C.R.; Raz, I.; Shulman, G.I.; et al. Type 2 diabetes mellitus. Nat. Rev. Dis. Primers 2015, 1, 15019. [Google Scholar] [CrossRef] [PubMed]
- Bray, G.A. Obesity increases risk for diabetes. Int. J. Obes. Relat. Metab. Disord. 1992, 16 (Suppl. 4), S13–S17. [Google Scholar]
- Kahn, S.E.; Zraika, S.; Utzschneider, K.M.; Hull, R.L. The beta cell lesion in type 2 diabetes: There has to be a primary functional abnormality. Diabetologia 2009, 52, 1003–1012. [Google Scholar] [CrossRef] [Green Version]
- Doria, A.; Patti, M.E.; Kahn, C.R. The emerging genetic architecture of type 2 diabetes. Cell Metab. 2008, 8, 186–200. [Google Scholar] [CrossRef] [Green Version]
- Burke, S.J.; Karlstad, M.D.; Collier, J.J. Pancreatic Islet Responses to Metabolic Trauma. Shock 2016, 46, 230–238. [Google Scholar] [CrossRef] [Green Version]
- Taylor, R. Type 2 Diabetes and Remission: Practical Management Guided by Pathophysiology. J. Intern. Med. 2020, 289, 754–770. [Google Scholar] [CrossRef]
- Upadhyay, J.; Polyzos, S.A.; Perakakis, N.; Thakkar, B.; Paschou, S.A.; Katsiki, N.; Underwood, P.; Park, K.H.; Seufert, J.; Kang, E.S.; et al. Pharmacotherapy of type 2 diabetes: An update. Metabolism 2018, 78, 13–42. [Google Scholar] [CrossRef]
- Unger, R.H. Lipotoxic diseases. Annu. Rev. Med. 2002, 53, 319–336. [Google Scholar] [CrossRef]
- Eldor, R.; DeFronzo, R.A.; Abdul-Ghani, M. In vivo actions of peroxisome proliferator-activated receptors: Glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care 2013, 36 (Suppl. 2), S162–S174. [Google Scholar] [CrossRef] [Green Version]
- Defronzo, R.A.; Tripathy, D.; Schwenke, D.C.; Banerji, M.; Bray, G.A.; Buchanan, T.A.; Clement, S.C.; Gastaldelli, A.; Henry, R.R.; Kitabchi, A.E.; et al. Prevention of diabetes with pioglitazone in ACT NOW: Physiologic correlates. Diabetes 2013, 62, 3920–3926. [Google Scholar] [CrossRef] [Green Version]
- DeFronzo, R.A.; Abdul-Ghani, M.A. Preservation of beta-cell function: The key to diabetes prevention. J. Clin. Endocrinol. Metab. 2011, 96, 2354–2366. [Google Scholar] [CrossRef] [Green Version]
- Lehmann, J.M.; Moore, L.B.; Smith-Oliver, T.A.; Wilkison, W.O.; Willson, T.M.; Kliewer, S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 1995, 270, 12953–12956. [Google Scholar] [CrossRef] [Green Version]
- Cristancho, A.G.; Lazar, M.A. Forming functional fat: A growing understanding of adipocyte differentiation. Nat. Rev. Mol. Cell Biol. 2011, 12, 722–734. [Google Scholar] [CrossRef]
- Croasdell, A.; Duffney, P.F.; Kim, N.; Lacy, S.H.; Sime, P.J.; Phipps, R.P. PPARgamma and the Innate Immune System Mediate the Resolution of Inflammation. PPAR Res. 2015, 2015, 549691. [Google Scholar] [CrossRef] [Green Version]
- Burke, S.J.; Batdorf, H.M.; Burk, D.H.; Noland, R.C.; Eder, A.E.; Boulos, M.S.; Karlstad, M.D.; Collier, J.J. db/db Mice Exhibit Features of Human Type 2 Diabetes That Are Not Present in Weight-Matched C57BL/6J Mice Fed a Western Diet. J. Diabetes Res. 2017, 2017, 8503754. [Google Scholar] [CrossRef] [Green Version]
- Obernier, J.A.; Baldwin, R.L. Establishing an appropriate period of acclimatization following transportation of laboratory animals. ILAR J. 2006, 47, 364–369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sims, E.K.; Hatanaka, M.; Morris, D.L.; Tersey, S.A.; Kono, T.; Chaudry, Z.Z.; Day, K.H.; Moss, D.R.; Stull, N.D.; Mirmira, R.G.; et al. Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains. Am. J. Physiol. Endocrinol. Metab. 2013, 305, E1495–E1511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burke, S.J.; Karlstad, M.D.; Regal, K.M.; Sparer, T.E.; Lu, D.; Elks, C.M.; Grant, R.W.; Stephens, J.M.; Burk, D.H.; Collier, J.J. CCL20 is elevated during obesity and differentially regulated by NF-kappaB subunits in pancreatic beta-cells. Biochim. Biophys. Acta 2015, 1849, 637–652. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burke, S.J.; Batdorf, H.M.; Burk, D.H.; Martin, T.M.; Mendoza, T.; Stadler, K.; Alami, W.; Karlstad, M.D.; Robson, M.J.; Blakely, R.D.; et al. Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet beta-cell de-differentiation. Mol. Metab. 2018, 14, 95–107. [Google Scholar] [CrossRef]
- Burke, S.J.; Batdorf, H.M.; Eder, A.E.; Karlstad, M.D.; Burk, D.H.; Noland, R.C.; Floyd, Z.E.; Collier, J.J. Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice. Am. J. Pathol. 2017, 187, 614–626. [Google Scholar] [CrossRef] [Green Version]
- White, U.; Fitch, M.D.; Beyl, R.A.; Hellerstein, M.K.; Ravussin, E. Adipose depot-specific effects of 16 weeks of pioglitazone on in vivo adipogenesis in women with obesity: A randomised controlled trial. Diabetologia 2021, 64, 159–167. [Google Scholar] [CrossRef] [PubMed]
- Scott, D.K.; Collier, J.J.; Doan, T.T.; Bunnell, A.S.; Daniels, M.C.; Eckert, D.T.; O’Doherty, R.M. A modest glucokinase overexpression in the liver promotes fed expression levels of glycolytic and lipogenic enzyme genes in the fasted state without altering SREBP-1c expression. Mol. Cell. Biochem. 2003, 254, 327–337. [Google Scholar] [CrossRef]
- Kim-Muller, J.Y.; Fan, J.; Kim, Y.J.; Lee, S.A.; Ishida, E.; Blaner, W.S.; Accili, D. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic beta cells in diabetic mice. Nat. Commun. 2016, 7, 12631. [Google Scholar] [CrossRef] [PubMed]
- Cinti, F.; Bouchi, R.; Kim-Muller, J.Y.; Ohmura, Y.; Sandoval, P.R.; Masini, M.; Marselli, L.; Suleiman, M.; Ratner, L.E.; Marchetti, P.; et al. Evidence of beta-Cell Dedifferentiation in Human Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2016, 101, 1044–1054. [Google Scholar] [CrossRef] [Green Version]
- Guo, S.; Dai, C.; Guo, M.; Taylor, B.; Harmon, J.S.; Sander, M.; Robertson, R.P.; Powers, A.C.; Stein, R. Inactivation of specific beta cell transcription factors in type 2 diabetes. J. Clin. Investig. 2013, 123, 3305–3316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Espinoza, S.E.; Wang, C.P.; Tripathy, D.; Clement, S.C.; Schwenke, D.C.; Banerji, M.A.; Bray, G.A.; Buchanan, T.A.; Henry, R.R.; Kitabchi, A.E.; et al. Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance. Age 2016, 38, 485–493. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tripathy, D.; Daniele, G.; Fiorentino, T.V.; Perez-Cadena, Z.; Chavez-Velasquez, A.; Kamath, S.; Fanti, P.; Jenkinson, C.; Andreozzi, F.; Federici, M.; et al. Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus: A randomised, double-blind, placebo-controlled, mechanistic study. Diabetologia 2013, 56, 2153–2163. [Google Scholar] [CrossRef] [Green Version]
- Ishida, H.; Takizawa, M.; Ozawa, S.; Nakamichi, Y.; Yamaguchi, S.; Katsuta, H.; Tanaka, T.; Maruyama, M.; Katahira, H.; Yoshimoto, K.; et al. Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress. Metabolism 2004, 53, 488–494. [Google Scholar] [CrossRef]
- Burke, S.J.; Batdorf, H.M.; Huang, T.Y.; Jackson, J.W.; Jones, K.A.; Martin, T.M.; Rohli, K.E.; Karlstad, M.D.; Sparer, T.E.; Burk, D.H.; et al. One week of continuous corticosterone exposure impairs hepatic metabolic flexibility, promotes islet beta-cell proliferation, and reduces physical activity in male C57BL/6J mice. J. Steroid Biochem. Mol. Biol. 2019, 195, 105468. [Google Scholar] [CrossRef]
- Fransson, L.; Franzen, S.; Rosengren, V.; Wolbert, P.; Sjoholm, A.; Ortsater, H. beta-Cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome. J. Endocrinol. 2013, 219, 231–241. [Google Scholar] [CrossRef] [Green Version]
- Vernochet, C.; Peres, S.B.; Davis, K.E.; McDonald, M.E.; Qiang, L.; Wang, H.; Scherer, P.E.; Farmer, S.R. C/EBPalpha and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists. Mol. Cell. Biol. 2009, 29, 4714–4728. [Google Scholar] [CrossRef] [Green Version]
- Masuzaki, H.; Paterson, J.; Shinyama, H.; Morton, N.M.; Mullins, J.J.; Seckl, J.R.; Flier, J.S. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001, 294, 2166–2170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bujalska, I.J.; Kumar, S.; Stewart, P.M. Does central obesity reflect “Cushing’s disease of the omentum”? Lancet 1997, 349, 1210–1213. [Google Scholar] [CrossRef]
- Kurushima, H.; Ramprasad, M.; Kondratenko, N.; Foster, D.M.; Quehenberger, O.; Steinberg, D. Surface expression and rapid internalization of macrosialin (mouse CD68) on elicited mouse peritoneal macrophages. J. Leukoc. Biol. 2000, 67, 104–108. [Google Scholar] [CrossRef] [PubMed]
- Martinez, F.O.; Helming, L.; Gordon, S. Alternative activation of macrophages: An immunologic functional perspective. Annu. Rev. Immunol. 2009, 27, 451–483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tchkonia, T.; Thomou, T.; Zhu, Y.; Karagiannides, I.; Pothoulakis, C.; Jensen, M.D.; Kirkland, J.L. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 2013, 17, 644–656. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Kim, K.A.; Kim, J.H.; Sul, H.S. Pref-1, a preadipocyte secreted factor that inhibits adipogenesis. J. Nutr. 2006, 136, 2953–2956. [Google Scholar] [CrossRef]
- 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]
- Ahmadian, M.; Suh, J.M.; Hah, N.; Liddle, C.; Atkins, A.R.; Downes, M.; Evans, R.M. PPARgamma signaling and metabolism: The good, the bad and the future. Nat. Med. 2013, 19, 557–566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Soccio, R.E.; Chen, E.R.; Lazar, M.A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 2014, 20, 573–591. [Google Scholar] [CrossRef] [Green Version]
- DeFronzo, R.A.; Inzucchi, S.; Abdul-Ghani, M.; Nissen, S.E. Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diabetes Vasc. Dis. Res. 2019, 16, 133–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DeFronzo, R.A.; Tripathy, D.; Schwenke, D.C.; Banerji, M.; Bray, G.A.; Buchanan, T.A.; Clement, S.C.; Henry, R.R.; Hodis, H.N.; Kitabchi, A.E.; et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 2011, 364, 1104–1115. [Google Scholar] [CrossRef] [PubMed]
- Hallakou, S.; Doare, L.; Foufelle, F.; Kergoat, M.; Guerre-Millo, M.; Berthault, M.F.; Dugail, I.; Morin, J.; Auwerx, J.; Ferre, P. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997, 46, 1393–1399. [Google Scholar] [CrossRef]
- Guan, H.P.; Li, Y.; Jensen, M.V.; Newgard, C.B.; Steppan, C.M.; Lazar, M.A. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat. Med. 2002, 8, 1122–1128. [Google Scholar] [CrossRef]
- Bajaj, M.; Suraamornkul, S.; Pratipanawatr, T.; Hardies, L.J.; Pratipanawatr, W.; Glass, L.; Cersosimo, E.; Miyazaki, Y.; DeFronzo, R.A. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes 2003, 52, 1364–1370. [Google Scholar] [CrossRef] [Green Version]
- Miyazaki, Y.; Matsuda, M.; DeFronzo, R.A. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care 2002, 25, 517–523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Evans-Molina, C.; Robbins, R.D.; Kono, T.; Tersey, S.A.; Vestermark, G.L.; Nunemaker, C.S.; Garmey, J.C.; Deering, T.G.; Keller, S.R.; Maier, B.; et al. Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Mol. Cell. Biol. 2009, 29, 2053–2067. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Orasanu, G.; Ziouzenkova, O.; Devchand, P.R.; Nehra, V.; Hamdy, O.; Horton, E.S.; Plutzky, J. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J. Am. Coll. Cardiol. 2008, 52, 869–881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ishida, E.; Kim-Muller, J.Y.; Accili, D. Pair Feeding, but Not Insulin, Phloridzin, or Rosiglitazone Treatment, Curtails Markers of beta-Cell Dedifferentiation in db/db Mice. Diabetes 2017, 66, 2092–2101. [Google Scholar] [CrossRef] [Green Version]
- Aronoff, S.; Rosenblatt, S.; Braithwaite, S.; Egan, J.W.; Mathisen, A.L.; Schneider, R.L. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: A 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000, 23, 1605–1611. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Collier, J.J.; Batdorf, H.M.; Merrifield, K.L.; Martin, T.M.; White, U.; Ravussin, E.; Burk, D.H.; Cooley, C.R.; Karlstad, M.D.; Burke, S.J. Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans. Biomedicines 2021, 9, 1189. https://doi.org/10.3390/biomedicines9091189
Collier JJ, Batdorf HM, Merrifield KL, Martin TM, White U, Ravussin E, Burk DH, Cooley CR, Karlstad MD, Burke SJ. Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans. Biomedicines. 2021; 9(9):1189. https://doi.org/10.3390/biomedicines9091189
Chicago/Turabian StyleCollier, J. Jason, Heidi M. Batdorf, Kaelan L. Merrifield, Thomas M. Martin, Ursula White, Eric Ravussin, David H. Burk, Chris R. Cooley, Michael D. Karlstad, and Susan J. Burke. 2021. "Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans" Biomedicines 9, no. 9: 1189. https://doi.org/10.3390/biomedicines9091189