Novel discovery of Averrhoa bilimbi ethanolic leaf extract in the stimulation of brown fat differentiation program in combating diet-induced obesity
Tóm tắt
Brown adipocytes are known to promote energy expenditure and limit weight gain to combat obesity. Averrhoa bilimbi, locally called belimbing buluh (DBB), is mainly used as an ethnomedicine in the treatment of metabolic disorders including diabetes mellitus, hypertension and obesity. The present study aims to investigate the browning activity on white adipocytes by A. bilimbi leaf extract and to evaluate the potential mechanisms. Ethanolic leaf extract of A. bilimbi was exposed to Myf5 lineage precursor cells to stimulate adipocyte differentiation. Protein expressions of brown adipocyte markers were determined through high content screening analysis and validated through western blotting. Mito Stress Test assay was conducted to evaluate the cellular oxygen consumption rate upon A. bilimbi treatment. A. bilimbi ethanolic leaf extract exhibited an adipogenesis effect similar to a PPARgamma agonist. It also demonstrated brown adipocyte differentiation in myoblastic Myf5-positive precursor cells. Expression of UCP1 and PRDM16 were induced. The basal metabolic rate and respiratory capacity of mitochondria were increased upon A. bilimbi treatment. The findings suggest that Averrhoa bilimbi ethanolic leaf extract induces adipocyte browning through PRDM16 activation and enhances mitochondria activity due to UCP1 up-regulation.
Tài liệu tham khảo
Seale P. Transcriptional regulatory circuits controlling Brown fat development and activation. Diabetes. 2015;64(7):2369–75.
Giralt M, Villarroya F. White, Brown, beige/Brite: different adipose cells for different functions? Endocrinology. 2013;154(9):2992–3000.
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961–7.
Baboota RK, Singh DP, Sarma SM, Kaur J, Sandhir R, Boparai RK, Kondepudi KK, Bishnoi M. Capsaicin induces "brite" phenotype in differentiating 3T3-L1 preadipocytes. PLoS One. 2014;9(7):e103093.
Lone J, Choi JH, Kim SW, Yun JW. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem. 2016;27:193–202.
Morton JF. Bilimbi In: Fruits of warm climates. Julia F. Morton, Miami, FL; 1987. p. 128–129.
Alhassan AM, Ahmed QU. Averrhoa bilimbi Linn.: a review of its ethnomedicinal uses, phytochemistry, and pharmacology. J Pharm Bioallied Sci. 2016;8(4):265–71.
Pushparaj P, Tan CH, Tan BK. Effects of Averrhoa bilimbi leaf extract on blood glucose and lipids in streptozotocin-diabetic rats. J Ethnopharmacol. 2000;72(1–2):69–76.
Sharma A, Huard C, Vernochet C, Ziemek D, Knowlton KM, Tyminski E, Paradis T, Zhang Y, Jones JEC, von Schack D, et al. Brown fat determination and development from muscle precursor cells by novel action of bone morphogenetic protein 6. PLoS One. 2014;9(3):e92608-e92608.
Ambili S, Subramoniam A, Nagarajan NS. Studies on the antihyperlipidemic properties of Averrhoa bilimbi fruit in rats. Planta Med. 2009;75(1):55–8.
Zakaria M, Mohd MA. In: Traditional Malay Medicinal Plants. Penerbit Fajar Bakti Sdn Bhd, Kuala Lumpur; 1994. p. 460–465.
Goh SH. In: Malaysian Medicinal Plants for the Treatment of Cardiovascular Diseases. Pelanduk Publications, Kuala Lumpur; 1995. p. 62–63.
Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 2012;15(3):395–404.
Xue Y, Xu X, Zhang XQ, Farokhzad OC, Langer R. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles. Proc Natl Acad Sci U S A. 2016;113(20):5552–7.
Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest. 2015;125(2):478–86.
Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, Kurokawa M, Won KJ, Seale P. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab. 2014;19(4):593–604.
Zhang Y, Xie C, Wang H, Foss RM, Clare M, George EV, Li S, Katz A, Cheng H, Ding Y, et al. Irisin exerts dual effects on browning and adipogenesis of human white adipocytes. Am J Physiol Endocrinol Metab. 2016;311(2):E530–41.
Dorn GW, Vega RB, Kelly DP. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev. 2015;29(19):1981–91.
Kim J, Fernand VE, Henagan TM, Shin J, Huypens P, Newman S, Gettys TW, Chang JS. Regulation of Brown and White adipocyte transcriptome by the transcriptional coactivator NT-PGC-1Î. PLoS One. 2016;11(7):e0159990.
Nam M, Akie TE, Sanosaka M, Craige SM, Kant S, Keaney JF Jr, Cooper MP. Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene expression. Sci Rep. 2017;7:2013:1–12.
Nickens KP, Wikstrom JD, Shirihai OS, Patierno SR, Ceryak S. A bioenergetic profile of non-transformed fibroblasts uncovers a link between death-resistance and enhanced spare respiratory capacity. Mitochondrion. 2013;13(6):662–7.
Hill BG, Dranka BP, Zou L, Chatham JC, Darley-Usmar VM. Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal. Biochem J. 2009;424(1):99–107.
Parker N, Crichton PG, Vidal-Puig AJ, Brand MD. Uncoupling protein-1 (UCP1) contributes to the basal proton conductance of brown adipose tissue mitochondria. J Bioenerg Biomembr. 2009;41(4):335–42.
Qin N, Chen Y, Jin MN, Zhang C, Qiao W, Yue XL, Duan HQ, Niu WY. Anti-obesity and anti-diabetic effects of flavonoid derivative (Fla-CN) via microRNA in high fat diet induced obesity mice. Eur J Pharm Sci. 2016;82:52–63.
Kang HW, Lee SG, Otieno D, Ha K. Flavonoids, Potential Bioactive Compounds, and Non-Shivering Thermogenesis. Nutrients. 2018;10(9):1168–1193. https://doi.org/10.3390/nu10091168.