Obesity and thermogenic adipose tissue plasticity in dogs

Main Article Content

Tania Quesada-López
Francesc Villarroya

Abstract

Obesity in pet dogs is a growing concern in veterinary medicine in developed countries. Obesity is associated with the expansion of white fat, the main tissue that stores metabolic energy in mammals. Brown and beige adipose tissues, which express thermogenic uncoupling protein-1, are oppositely related to obesity due to their thermogenic activity and associated energy expenditure properties. Dogs possess high amounts of brown adipose tissue early after birth; however, its involution with aging causes adult dogs to possess minimal active brown fat. However, adult dogs retain a remarkable capacity to activate the browning of adipose tissue depots in response to sustained β-adrenergic stimulation or other inducers, such as cannabinoid receptor-1 inhibitors. Therefore, dogs retain the capacity of adipose tissue plasticity to acquire thermogenic properties, which should be considered when developing obesity prevention and/or treatment strategies for dogs.

Keywords:
Dogs, Obesity, brown adipose tissue, beige adipose tissue, β-adrenergic receptors

Article Details

References

German AJ. The growing problem of obesity in dogs and cats. Journal of Nutrition. 2006;136(7)Suppl:1940S-1946S. doi: 10.1093/jn/136.7.1940S. DOI: https://doi.org/10.1093/jn/136.7.1940S

McGreevy PD, Thomson PC, Pride C, Fawcett A, Grassi T, Jones B. Prevalence of obesity in dogs examined by Australian veterinary practices and the risk factors involved. Veterinary Record. 2005;156:695–702. doi: 10.1136/vr.156.22.695. DOI: https://doi.org/10.1136/vr.156.22.695

Lund EM, Armstrong PJ, Kirk CA, Klausner JS. Prevalence and risk factors for obesity in adult dogs from private US veterinary practices. International Journal of Applied Research in Veterinary Medicine. 2006;4:177–186. PMID: 10319174.

Colliard L, Ancel J, Benet JJ, Paragon BM, Blanchard G. Risk factors for obesity in dogs in France. Journal of Nutrition. 2006;136:1951S–1954S. doi: 10.1093/jn/136.7.1951S. DOI: https://doi.org/10.1093/jn/136.7.1951S

Mao J, Xia Z, Chen J, Yu J. Prevalence and risk factors for canine obesity surveyed in veterinary practices in Beijing, China. Preventive Veterinary Medicine. 2013;112:438–442. doi: 10.1016/j.prevetmed.2013.08.012. DOI: https://doi.org/10.1016/j.prevetmed.2013.08.012

Montoya-Alonso JA, Bautista-Castano I, Pena C, Suarez L, Juste MC, Tvarijonaviciute A. Prevalence of canine obesity, obesity-related metabolic dysfunction, and relationship with owner obesity in an obesogenic region of Spain. Frontiers in Veterinary Science. 2017;4:59. doi: 10.3389/fvets.2017.00059. DOI: https://doi.org/10.3389/fvets.2017.00059

Tvarijonaviciute A, Ceron JJ, Holden SL, Cuthbertson DJ, Biourge V, Morris PJ, German AJ. Obesity-related metabolic dysfunction in dogs: A comparison with human metabolic syndrome. BMC Veterinary Research. 2012;8:147. doi: 10.1186/1746-6148-8-147. DOI: https://doi.org/10.1186/1746-6148-8-147

German AJ, Blackwell E, Evans M, Westgarth C. Overweight dogs are more likely to display undesirable behaviours: Results of a large online survey of dog owners in the UK. Journal of Nutritional Science. 2017;6:e14. doi: 10.1017/jns.2017.5. DOI: https://doi.org/10.1017/jns.2017.5

Stachowiak M, Szczerbal I, Switonski M. Genetics of adiposity in large animal models for human obesity-studies on pigs and dogs. Progress in Molecular Biology and Translational Science. 2016;140:233–270. doi: 10.1016/bs.pmbts.2016.01.001. DOI: https://doi.org/10.1016/bs.pmbts.2016.01.001

Wallis N, Raffan E. The genetic basis of obesity and related metabolic diseases in humans and companion animals. Genes (Basel). 2020;11:1378. doi: 10.3390/genes11111378. DOI: https://doi.org/10.3390/genes11111378

Frühbeck G. Overview of adipose tissue and its role in obesity and metabolic disorders. Methods of Molecular Biology. 2008;456:1-22. doi: 10.1007/978-1-59745-245-8_1. DOI: https://doi.org/10.1007/978-1-59745-245-8_1

Ishioka K, Soliman MM, Sagawa M, Nakadomo F, Shibata H, Honjoh T, Hashimoto A, Kitamura H, Kinura K, Saito M. Experimental and clinical studies on plasma leptin in obese dogs. Journal of Veterinary Medical Science. 2002;64:349–353. doi: 10.1292/jvms.64.349. DOI: https://doi.org/10.1292/jvms.64.349

Gayet C, Leray V, Saito M, Siliart B, Nguyen P. The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-g target genes, in dogs. British Journal of Nutrition. 2007;98:497–503. doi: 10.1017/S000711450772514X. DOI: https://doi.org/10.1017/S000711450772514X

Motomura M, Shimokawa F, Kobayashi T, Yamashita Y, Mizoguchi I, Sato Y, Murakami Y, Shimizu I, Matsui T, Murakami M, Funaba M. Relationships between expression levels of genes related to adipogenesis and adipocyte function in dogs. Molecular Biology Reports. 2019;46:4771-4777. doi: 10.1007/s11033-019-04923-3. DOI: https://doi.org/10.1007/s11033-019-04923-3

Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiological Reviews. 2004;84:277-359. doi: 10.1152/physrev.00015.2003. DOI: https://doi.org/10.1152/physrev.00015.2003

Whittle AJ, López M, Vidal-Puig A. Using brown adipose tissue to treat obesity -the central issue. Trends in Molecular Medicine. 2011;17:405-411. doi: 10.1016/j.molmed.2011.04.001. DOI: https://doi.org/10.1016/j.molmed.2011.04.001

Enerbäck S. Human brown adipose tissue. Cell Metabolism. 2010;11:248-252. doi: 10.1016/j.cmet.2010.03.008. DOI: https://doi.org/10.1016/j.cmet.2010.03.008

Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, Butler SD, Jiang CS, Vaughan R, Schöder H, Mark A, Cohen P. Brown adipose tissue is associated with cardiometabolic health. Nature Medicine. 2021;27:58-65. doi: 10.1038/s41591-020-1126-7. DOI: https://doi.org/10.1038/s41591-020-1126-7

Berg F, Gustafson U, Andersson L. The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: a genetic explanation for poor thermoregulation in piglets. PLoS Genetics. 2006;2:e129. doi: 10.1371/journal.pgen.0020129. DOI: https://doi.org/10.1371/journal.pgen.0020129

Gaudry MJ, Jastroch M, Treberg JR, Hofreiter M, Paijmans JLA, Starrett J, Wales N, Signore AV, Springer MS, Campbell KL. Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades. Science Advances. 2017;3,e1602878. doi: 10.1126/sciadv.1602878. DOI: https://doi.org/10.1126/sciadv.1602878

Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for different functions? Endocrinology. 2013;154:2992-3000. doi: 10.1210/en.2013-1403. DOI: https://doi.org/10.1210/en.2013-1403

Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366-376. doi: 10.1016/j.cell.2012.05.016. DOI: https://doi.org/10.1016/j.cell.2012.05.016

Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, Vetrivelan R, Lu GZ, Laznik-Bogoslavski D, Hasenfuss SC, Kajimura S, Gygi SP, Spiegelman BM. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell. 2015;163:643-655. doi: 10.1016/j.cell.2015.09.035. DOI: https://doi.org/10.1016/j.cell.2015.09.035

Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Reports. 2013;5:1196-1203. doi: 10.1016/j.celrep.2013.10.044. DOI: https://doi.org/10.1016/j.celrep.2013.10.044

Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, Cinti S. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. American Journal of Physiology Endocrinology and Metabolism. 2010;298:E1244-E1253. doi: 10.1152/ajpendo.00600.2009. DOI: https://doi.org/10.1152/ajpendo.00600.2009

Rosenwald M, Perdikari A, Rülicke T, Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nature Cell Biology. 2013;15:659-667. doi: 10.1038/ncb2740. DOI: https://doi.org/10.1038/ncb2740

Xue B, Rim JS, Hogan JC, Coulter AA, Koza RA, Kozak LP. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. Journal of Lipid Research. 2007;48:41-51. doi: 10.1194/jlr.M600287-JLR200. DOI: https://doi.org/10.1194/jlr.M600287-JLR200

Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerbäck S. Evidence for two types of brown adipose tissue in humans. Nature Medicine. 2013;19:631-634. doi: 10.1038/nm.3017. DOI: https://doi.org/10.1038/nm.3017

Villarroya F, Vidal-Puig A. Beyond the sympathetic tone: the new brown fat activators. Cell Metabolism. 2013;17:638-643. doi: 10.1016/j.cmet.2013.02.020. DOI: https://doi.org/10.1016/j.cmet.2013.02.020

Saito M, Matsushita M, Yoneshiro T, Okamatsu-Ogura Y. Brown adipose tissue, diet-induced thermogenesis, and thermogenic food ingredients: from mice to men. Frontiers in Endocrinology. 2020;11:222. doi: 10.3389/fendo.2020.00222. DOI: https://doi.org/10.3389/fendo.2020.00222

Ashwell M, Stirling D, Freeman S, Holloway BR. Immunological, histological and biochemical assessment of brown adipose tissue activity in neonatal, control and beta-stimulant-treated adult dogs. International Journal of Obesity. 1987;11:357-365. PMID: 2889691.

Holloway BR, Stribling D, Freeman S, Jamieson L. The thermogenic role of adipose tissue in the dog. International Journal of Obesity. 1985;9:423-432.

Astrup A, Bülow J, Christensen NJ. The effect of non-esterified long-chain fatty acids on blood flow and thermogenesis in brown adipose tissue in the young dog. Acta Physiologica Scandinavica. 1985;124:81-85. doi: 10.1111/j.1748-1716.1985.tb07634x. DOI: https://doi.org/10.1111/j.1748-1716.1985.tb07634.x

Champigny O, Ricquier D, Blondel O, Mayers RM, Briscoe MG, Holloway BR. Beta 3-adrenergic receptor stimulation restores message and expression of brown-fat mitochondrial uncoupling protein in adult dogs. Proceedings of the National Academy of Sciences USA. 1991;88:10774-10777. doi: 10.1073/pnas.88.23.10774. PMID: 3007382. DOI: https://doi.org/10.1073/pnas.88.23.10774

Symonds ME, Pope M, Budge H. The ontogeny of brown adipose tissue. Annual Reviews of Nutrition. 2015;35:295-320. doi: 10.1146/annurev-nutr-071813-105330. DOI: https://doi.org/10.1146/annurev-nutr-071813-105330

Amorim I, Faria F, Taulescu M, Taulescu C, Gärtner F. Nipple hibernoma in a dog: a case report with literature review. Frontiers in Veterinary Science. 2021;8:627288. doi: 10.3389/fvets.2021.627288. DOI: https://doi.org/10.3389/fvets.2021.627288

Collins S, Cao W, Robidoux J. Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Molecular Endocrinology. 2004;18:2123-2131. doi: 10.1210/me.2004-0193. DOI: https://doi.org/10.1210/me.2004-0193

Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, English J, Chatman, K, Trauger S.A, Doria A, Kolodny G. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metabolism. 2015;21:33–38. doi: 10.1016/j.cmet.2014.12.009. DOI: https://doi.org/10.1016/j.cmet.2014.12.009

Galitzky J, Carpéné C, Bousquet-Mélou A, Berlan M, Lafontan M. Differential activation of beta 1-, beta 2- and beta 3-adrenoceptors by catecholamines in white and brown adipocytes. Fundamental and Clinical Pharmacology. 1995;9:324-331. doi: 10.1111/j.1472-8206.1995.tb00506.x. DOI: https://doi.org/10.1111/j.1472-8206.1995.tb00506.x

Sasaki N, Uchida E, Niiyama M, Yoshida T, Saito M. Anti-obesity effects of selective agonists to the beta 3-adrenergic receptor in dogs. II. Recruitment of thermogenic brown adipocytes and reduction of adiposity after chronic treatment with a beta 3-adrenergic agonist. Journal of Veterinary Medical Science. 1998;60:465-469. doi: 10.1292/jvms.60.465. DOI: https://doi.org/10.1292/jvms.60.465

Carpéné C, Galitzky J, Fontana E, Atgié C, Lafontan M, Berlan M. Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells. Naunyn Schmiedeberg’s Archives of Pharmacology. 1999;359:310-321. doi: 10.1007/pl00005357. DOI: https://doi.org/10.1007/PL00005357

Omachi A, Ishioka K, Uozumi A, Kamikawa A, Toda C, Kimura K, Saito M. Beta3-adrenoceptor agonist AJ-9677 reduces body fat in obese Beagles. Research in Veterinary Science. 2007;83:5-11. doi: 10.1016/j.rvsc.2006.10.003. DOI: https://doi.org/10.1016/j.rvsc.2006.10.003

Omachi A, Matsushita Y, Kimura K, Saito M. Role of uncoupling protein 1 in the anti-obesity effect of beta3-adrenergic agonist in the dog. Research in Veterinary Science. 2008;85:214-219. doi: 10.1016/j.rvsc.2007.11.003. DOI: https://doi.org/10.1016/j.rvsc.2007.11.003

Toseland CD, Campbell S, Francis I, Bugelski PJ, Mehdi N. Comparison of adipose tissue changes following administration of rosiglitazone in the dog and rat. Diabetes Obesity and Metabolism. 2001;3:163-170. doi: 10.1046/j.1463-1326.2001.00117. DOI: https://doi.org/10.1046/j.1463-1326.2001.00117.x

Lefterova MI, Haakonsson AK, Lazar MA, Mandrup S. PPAR-gamma and the global map of adipogenesis and beyond. Trends in Endocrinology and Metabolism. 2014;25:293-302. doi: 10.1016/j.tem.2014.04.001. DOI: https://doi.org/10.1016/j.tem.2014.04.001

Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2003;284:R345-R353. doi:10.1152/ajpregu.00545.2002. DOI: https://doi.org/10.1152/ajpregu.00545.2002

Richey JM, Woolcott OO, Stefanovski D, Harrison LN, Zheng D, Lottati M, Hsu IR, Kim SP, Kabir M, Catalano KJ, Chiu JD, Ionut V, Kolka C, Mooradian V, Bergman RN. Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs. American Journal of Physiology-Endocrinology and Metabolism. 2009;296:E1311-E1318. doi:10.1152/ajpendo.90972.2008. DOI: https://doi.org/10.1152/ajpendo.90972.2008

Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397. doi: 10.1016/S0140-6736(05)66374-X. DOI: https://doi.org/10.1016/S0140-6736(05)66374-X

King A. Neuropsychiatric adverse effects signal the end of the line for rimonabant. Nature Reviews Cardiology. 2010;7:602. doi: 10.1038/nrcardio.2010.148. DOI: https://doi.org/10.1038/nrcardio.2010.148

Iyer MS, Paszkiewicz RL, Bergman RN, Richey JM, Woolcott OO, Asare-Bediako I, Wu Q, Kim SP, Stefanovski D, Kolka CM, Clegg DJ, Kabir M. Activation of NPRs and UCP1-independent pathway following CB1R antagonist treatment is associated with adipose tissue beiging in fat-fed male dogs. American Journal of Physiology-Endocrinology and Metabolism. 2019;317:E535-E547. doi: 10.1152/ajpendo.00539.2018. DOI: https://doi.org/10.1152/ajpendo.00539.2018

Yen M, Ewald MBJ. Toxicity of weight loss agents. Journal of Medical Toxicology. 2012;8:145-152. doi: 10.1007/s13181-012-0213-7. DOI: https://doi.org/10.1007/s13181-012-0213-7

Martin AR, Chung S, Koehler K. Is exercise a match for cold exposure? Common molecular framework for adipose tissue browning. International Journal of Sports Medicine. 2020;41(7):427-442. doi: 10.1055/a-1100-7118. DOI: https://doi.org/10.1055/a-1100-7118