Download PDF
Drug Res (Stuttg) 2019; 69(05): 265-270
DOI: 10.1055/a-0667-8744
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Duration of a ”Brown-Like” Phenotype of White Adipose Tissue Induced by the β3 Agonist CL-316,243

Wojciech Danysz
1   Merz Pharmaceuticals, Frankfurt, Germany
,
Kang Jinlai
2   HD Biosciences Ltd, Shanghai, China
,
Fugang Li
2   HD Biosciences Ltd, Shanghai, China
› Author Affiliations
Further Information

Publication History

received 25 June 2018

accepted 27 July 2018

Publication Date:
06 September 2018 (online)

Also available at
   Permissions and Reprints

Abstract

“Browning” i. e. the transformation of white adipose tissue into brown-like adipose tissue could induce efficient burning of excess fat reserves via induction of non-shivering thermogenesis. For example, activation of ß3 adrenergic receptors has been show to induce such changes, however, it is still not clear, how long after termination of such a treatment, beneficial effects might be maintained. To address this question, we treated rats s.c. for 2 weeks with the ß3 agonist CL-316,243 at 1 mg/kg and assessed interscapular brown fat and inguinal white fat pads weight, UCP-1 (a marker for the brown-like fat phenotype) using immunohistochemistry and H&E staining, at different intervals after treatment termination.

One 1 day after the treatment cessation there was a decrease of inguinal white fat pad weight and increase of interscapular fat pad. This change vanished at 7 days for inguinal pad and at 14 days for interscapular pad. Histological analysis of interscapular pads showed increased UCP-1 staining and brown-like morphology in H&E staining slices at 1 day, but not other time points. In case of inguinal pad there were brown-like features in H&E slices at 1 day and less after 7 days, but absent at 14 days. UCP-1 staining was only detected 1 day after the treatment.

In conclusion, the present results indicate that browning-like changes of white fat may be short lasting after treatment termination and could require maintenance treatment of inductor to achieve desired therapeutic effect. This might be a serious shortcoming of potential therapeutic use.

Key words

WAT - BAT - browning - UCP-1 - H&E
 

  • References

  • 1 Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277-359
    CrossrefPubMedGoogle Scholar
  • 2 Yoneshiro T, Aita S, Matsushita M. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013; 123: 3404-3408
    CrossrefPubMedGoogle Scholar
  • 3 Orava J, Nuutila P, Lidell ME. et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011; 14: 272-279
    CrossrefPubMedGoogle Scholar
  • 4 Muzik O, Mangner TJ, Leonard WR. et al. 15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat. J Nucl Med 2013; 54: 523-531
    CrossrefPubMedGoogle Scholar
  • 5 van der Lans AA, Hoeks J, Brans B. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest 2013; 123: 3395-3403
    CrossrefPubMedGoogle Scholar
  • 6 Sidossis LS, Porter C, Saraf MK. et al. Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 2015; 22: 219-227
    CrossrefPubMedGoogle Scholar
  • 7 Ramage LE, Akyol M, Fletcher AM. et al. Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab 2016; 24: 130-141
    CrossrefPubMedGoogle Scholar
  • 8 Sugita J, Yoneshiro T, Hatano T. et al. Grains of paradise (Aframomum melegueta) extract activates brown adipose tissue and increases whole-body energy expenditure in men. Br J Nutr 2013; 110: 733-738
    CrossrefPubMedGoogle Scholar
  • 9 Whiting S, Derbyshire E, Tiwari BK. Capsaicinoids and capsinoids. A potential role for weight management? A systematic review of the evidence. Appetite 2012; 59: 341-348
    CrossrefPubMedGoogle Scholar
  • 10 Li S, Li Y, Xiang L. et al. Sildenafil induces browning of subcutaneous white adipose tissue in overweight adults. Metabolism 2018; 78: 106-117
    CrossrefPubMedGoogle Scholar
  • 11 Gnad T, Scheibler S, von Kugelgen I. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 2014; 516: 395-399
    PubMedGoogle Scholar
  • 12 Himms-Hagen J, Melnyk A, Zingaretti MC. et al. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol 2000; 279: C670-C681
    CrossrefPubMedGoogle Scholar
  • 13 Koh YJ, Park BH, Park JH. et al. Activation of PPAR gamma induces profound multilocularization of adipocytes in adult mouse white adipose tissues. Exp Mol Med 2009; 41: 880-895
    CrossrefPubMedGoogle Scholar
  • 14 Perwitz N, Wenzel J, Wagner I. et al. Cannabinoid type 1 receptor blockade induces transdifferentiation towards a brown fat phenotype in white adipocytes. Diabetes Obes Metab 2010; 12: 158-166
    CrossrefPubMedGoogle Scholar
  • 15 Boon MR, van den Berg SA, Wang Y. et al. BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One 2013; 8: e74083
    CrossrefPubMedGoogle Scholar
  • 16 Liu X, Perusse F, Bukowiecki LJ. Mechanisms of the antidiabetic effects of the beta 3-adrenergic agonist CL-316243 in obese Zucker-ZDF rats. Am J Physiol 1998; 274: R1212-R1219
    PubMedGoogle Scholar
  • 17 Yoshida T, Umekawa T, Kumamoto K. et al. beta 3-Adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers. Am J Physiol 1998; 274: E469-E475
    PubMedGoogle Scholar
  • 18 Weyer C, Gautier JF, Danforth Jr E. Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes–an update. Diabetes Metab 1999; 25: 11-21
    PubMedGoogle Scholar
  • 19 de Souza CJ, Burkey BF. Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans. Curr Pharm Des 2001; 7: 1433-1449
    CrossrefPubMedGoogle Scholar
  • 20 Danysz W, Han Y, Li F. et al. Browning of white adipose tissue induced by the β3 agonist CL-316,243 after local and systemic treatment - PK-PD relationship. Biochim Biophys Acta 2018; 1864: 2972-2982
    PubMedGoogle Scholar
  • 21 Himms-Hagen J, Cui J, Danforth Jr. E. et al. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol 1994; 266: R1371-R1382
    PubMedGoogle Scholar
  • 22 Nagase I, Yoshida T, Kumamoto K. et al. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist. J Clin Invest 1996; 97: 2898-2904
    CrossrefPubMedGoogle Scholar
  • 23 Ghorbani M, Himms-Hagen J. Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats. Int J Obes Relat Metab Disord 1997; 21: 465-475
    CrossrefPubMedGoogle Scholar
  • 24 Murano I, Barbatelli G, Giordano A. et al. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat 2009; 214: 171-178
    CrossrefPubMedGoogle Scholar
  • 25 Rosenwald M, Perdikari A, Rulicke T. et al. Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol 2013; 15: 659-667
    CrossrefPubMedGoogle Scholar
  • 26 Petruzzelli M, Schweiger M, Schreiber R. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 2014; 20: 433-447
    CrossrefPubMedGoogle Scholar