Brown preadipocyte transplantation locally ameliorates obesity

Background Brown adipose tissue (BAT) is a potential target for anti-obesity treatments. Previous studies have shown that BAT activation causes an acute metabolic boost and reduces adiposity. Furthermore, BAT and BAT-derived cell transplantation reportedly help treat obesity by regulating glucose and fatty acid metabolism. However, since BAT transplantation leads to whole-body weight loss, we speculated that earlier approaches cause a generalized and unnecessary fat tissue loss, including in breast and hip tissues.

Methods We transplanted white adipose tissue-derived or BAT-derived preadipocytes prepared from C57BL/6 mice into one side of the inguinal fat pads of an obese mouse model (db/db mice) to examine whether it would cause fat loss at the peri-transplant site (n=5 each). The same volume of phosphate-buffered saline was injected as a control on the other side. Six weeks after transplantation, the inguinal fat pad was excised and weighed. We also measured the concentrations of glucose, triglycerides, fatty acids, and total cholesterol in the peripheral blood.

Results BAT-derived preadipocytes showed abundant mitochondria and high levels of mitochondrial membrane uncoupling protein 1 expression, both in vivo and in vitro, with a remarkable reduction in weight of the inguinal fat pad after transplantation (0.17±0.12 g, P=0.043). Only free fatty acid levels tended to decrease in the BAT-transplanted group, but the difference was not significant (P=0.11).

Conclusions Our results suggest that brown adipocytes drive fat degradation around the transplantation site. Thus, local transplantation of BAT-derived preadipocytes may be useful for treating obesity, as well as in cosmetic treatments.

Keywords

Adipose tissue, brown - Adipocytes - Transplantation - Weight loss - Obesity

Publikationsverlauf

Eingereicht: 18. November 2020

Angenommen: 04. Mai 2021

Artikel online veröffentlicht:
21. März 2022

• REFERENCES

• 1 World Health Organization (WHO). Obesity and overweight [Internet]. Geneva: WHO c2017 [cited 2020 Oct 30]. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
• 2 Thomou T, Mori MA, Dreyfuss JM. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 2017; 542: 450-5
• 3 Grundy SM, Adams-Huet B, Vega GL. Variable contributions of fat content and distribution to metabolic syndrome risk factors. Metab Syndr Relat Disord 2008; 6: 281-8
• 4 Shiffman MA. Prevention and treatment of liposuction complications. In: Shiffman MA, Di Giuseppe A. Liposuction–principles and practice. 1st. New York: Springer; 2006: 333-41
• 5 Jayasinghe S, Guillot T, Bissoon L. et al. Mesotherapy for local fat reduction. Obes Rev 2013; 14: 780-91
• 6 Frayn KN. Fat as a fuel: emerging understanding of the adipose tissue-skeletal muscle axis. Acta Physiol (Oxf) 2010; 199: 509-18
• 7 Heaton GM, Wagenvoord RJ, Kemp Jr A. et al. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem 1978; 82: 515-21
• 8 Bartelt A, Bruns OT, Reimer R. et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011; 17: 200-5
• 9 van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM. et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360: 1500-8
• 10 Collins S, Surwit RS. The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog Horm Res 2001; 56: 309-28
• 11 Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277-359
• 12 Zingaretti MC, Crosta F, Vitali A. et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009; 23: 3113-20
• 13 Zhang Y, Xu Q, Liu YH. et al. Medium-chain triglyceride activated brown adipose tissue and induced reduction of fat mass in C57BL/6J mice fed high-fat diet. Biomed Environ Sci 2015; 28: 97-104
• 14 Virtanen KA, Lidell ME, Orava J. et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518-25
• 15 Silva FJ, Holt DJ, Vargas V. et al. Metabolically active human brown adipose tissue derived stem cells. Stem Cells 2014; 32: 572-81
• 16 Zhu Z, Spicer EG, Gavini CK. et al. Enhanced sympathetic activity in mice with brown adipose tissue transplantation (transBATation). Physiol Behav 2014; 125: 21-9
• 17 Stanford KI, Middelbeek RJ, Townsend KL. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 2013; 123: 215-23
• 18 Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition 2003; 19: 457-66
• 19 Liu X, Wang S, You Y. et al. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology 2015; 156: 2461-9
• 20 Ghorbani M, Teimourian S, Farzad R. et al. Apparent histological changes of adipocytes after treatment with CL 316,243, a β-3-adrenergic receptor agonist. Drug Des Devel Ther 2015; 9: 669-76
• 21 Harper JA, Dickinson K, Brand MD. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev 2001; 2: 255-65
• 22 Symonds ME, Aldiss P, Dellschaft N. et al. Brown adipose tissue development and function and its impact on reproduction. J Endocrinol 2018; 238: R53-62
• 23 Sornelli F, Fiore M, Chaldakov GN. et al. Adipose tissue-derived nerve growth factor and brain-derived neurotrophic factor: results from experimental stress and diabetes. Gen Physiol Biophys 2009; 28 Spec No: 179-83
• 24 Kopecky J, Flachs P, Bardova K. et al. Modulation of lipid metabolism by energy status of adipocytes: implications for insulin sensitivity. Ann N Y Acad Sci 2002; 967: 88-101
• 25 Kikai M, Yamada H, Wakana N. et al. Adrenergic receptormediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE -/- mice. Biochem Biophys Res Commun 2018; 497: 1097-103
• 26 Min SY, Kady J, Nam M. et al. Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 2016; 22: 312-8
• 27 Muhsin NIA, Bentley L, Bai Y. et al. A novel mutation in the mouse Pcsk1 gene showing obesity and diabetes. Mamm Genome 2020; 31: 17-29
• 28 Shi Y, Yuan Y, Dong Z. et al. The fate of fat grafts in different recipient areas: subcutaneous plane, fat pad, and muscle. Dermatol Surg 2016; 42: 535-42
• 29 Gunawardana SC, Piston DW. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 2012; 61: 674-82