Adipocytes regulate lipid metabolism according to physiological energy requirements. A dysfunctional lipid metabolism can lead to obesity and its complications such as hepatic steatosis, diabetes, and hyperlipidemia. In our study, the impact of Platycodon grandiflorus root ethanol extract (PGH) on lipid excretion and thermogenesis-related markers in diet-induced obesity mice was analyzed. Our data show that PGH elevated fatty acid uptake in epididymal adipose tissue by increasing Cd36, Slc27a1, Ffar2, and Ffar4 expression, which led to decreased blood free fatty acid concentrations. Moreover, PGH normalized body weight and fat mass in diet-induced obese mice by increasing lipolysis (Plin1, Atgl, and Hsl) and fatty acid oxidation. Changes in the levels of browning-related genes, enzyme activity of carnitine palmitoyltransferase, and the overall transcriptome (Bmp4, Cidec, Ucp3, Sirt3, and Cox4i1) led to promote brown adipose tissue-like features (browning) in epididymal white adipose tissue and enhanced energy expenditure. Our results suggest that PGH promotes lipid excretion and thermogenic function in high-fat diet-induced obese mice, which are mediated by regulation of fat metabolism.
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References
1.
JungUJ, ChoiMS: Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci, 2014; 15:6184–6223.
2.
LarsenJ, HyllebergB, NgK, DamsboP: Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care, 2001; 24:1416–1421.
3.
FujiokaS, MatsuzawaY, TokunagaK, TaruiS: Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism, 1987; 36:54–59.
4.
LakkaHM, LaaksonenDE, LakkaTA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA, 2002; 288:2709–2716.
5.
LiuQ, BengmarkS, QuS: The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis, 2010; 9:42.
6.
NedergaardJ, CannonB: The browning of white adipose tissue: Some burning issues. Cell Metab, 2014; 20:396–407.
7.
WangS, LiangX, YangQ, et al.: Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) alpha1. Int J Obes (Lond), 2015; 39:967–976.
8.
SchulzTJ, TsengYH: Brown adipose tissue: Development, metabolism and beyond. Biochem J, 2013; 453:167–178.
9.
ParkYS, YoonY, AhnHS: Platycodon grandiflorum extract represses up-regulated adipocyte fatty acid binding protein triggered by a high fat feeding in obese rats. World J Gastroenterol, 2007; 13:3493–3499.
10.
LeeJS, ChoiMS, SeoKI, et al.: Platycodi radix saponin inhibits alpha-glucosidase in vitro and modulates hepatic glucose-regulating enzyme activities in C57BL/KsJ-db/db mice. Arch Pharm Res, 2014; 37:773–782.
11.
QinH, DuX, ZhangY, WangR: Platycodin D, a triterpenoid saponin from Platycodon grandiflorum, induces G2/M arrest and apoptosis in human hepatoma HepG2 cells by modulating the PI3K/Akt pathway. Tumour Biol, 2014; 35:1267–1274.
12.
ZhangL, WangY, YangD, et al.: Platycodon grandiflorus—An ethnopharmacological, phytochemical and pharmacological review. J Ethnopharmacol, 2015; 164:147–161.
13.
KimYJ, ChoiJY, RyuR, et al.: Platycodon grandiflorus root extract attenuates body fat mass, hepatic steatosis and insulin resistance through the interplay between the liver and adipose tissue. Nutrients, 2016; 8:E532.
14.
FolchJ, LeesM, Sloane StanleyGH: A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem, 1957; 226:497–509.
15.
HulcherFH, OlesonWH: Simplified spectrophotometric assay for microsomal 3-hydroxy-3-methylglutaryl CoA reductase by measurement of coenzyme A. J Lipid Res, 1973; 14:625–631.
16.
MarkwellMA, McGroartyEJ, BieberLL, TolbertNE: The subcellular distribution of carnitine acyltransferases in mammalian liver and kidney. A new peroxisomal enzyme. J Biol Chem, 1973; 248:3426–3432.
17.
RyuR, JeongTS, KimYJ, et al.: Beneficial effects of pterocarpan-high soybean leaf extract on metabolic syndrome in overweight and obese korean subjects: Randomized controlled trial. Nutrients, 2016; 8:E734.
18.
ParkHG, BakEJ, WooGH, et al.: Licochalcone E has an antidiabetic effect. J Nutr Biochem, 2012; 23:759–767.
19.
PengJ, LuoF, RuanG, PengR, LiX: Hypertriglyceridemia and atherosclerosis. Lipids Health Dis, 2017; 16:233.
20.
KlettEL, LeeMH, AdamsDB, ChavinKD, PatelSB: Localization of ABCG5 and ABCG8 proteins in human liver, gall bladder and intestine. BMC Gastroenterol, 2004; 4:21.
21.
KruitJK, GroenAK, van BerkelTJ, KuipersF: Emerging roles of the intestine in control of cholesterol metabolism. World J Gastroenterol, 2006; 12:6429–6439.
22.
SaneAT, SinnettD, DelvinE, et al.: Localization and role of NPC1L1 in cholesterol absorption in human intestine. J Lipid Res, 2006; 47:2112–2120.
23.
SilversteinRL, FebbraioM: CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal, 2009; 2:re3.
24.
MontoudisA, SeidmanE, BoudreauF, et al.: Intestinal fatty acid binding protein regulates mitochondrion beta-oxidation and cholesterol uptake. J Lipid Res, 2008; 49:961–972.
25.
MotojimaK, PassillyP, PetersJM, GonzalezFJ, LatruffeN: Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem, 1998; 273:16710–16714.
26.
FeingoldKR, GrunfeldC: Introduction to lipids and lipoproteins. In: Endotext. (DeGroot LJ, ChrousosG, DunganK, et al., eds.). South Dartmouth, MA, MDText.com Inc., 2000, pp. 1–20.
27.
AltmannSW, DavisHRJr., ZhuLJ, et al.: Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science, 2004; 303:1201–1204.
28.
WangDQ: Regulation of intestinal cholesterol absorption. Annu Rev Physiol, 2007; 69:221–248.
29.
ZechnerR, ZimmermannR, EichmannTO, et al.: FAT SIGNALS—Lipases and lipolysis in lipid metabolism and signaling. Cell Metab, 2012; 15:279–291.
30.
WalczakR, TontonozP: PPARadigms and PPARadoxes: Expanding roles for PPARgamma in the control of lipid metabolism. J Lipid Res, 2002; 43:177–186.
31.
BodisK, KahlS, SimonMC, et al.: Reduced expression of stearoyl-CoA desaturase-1, but not free fatty acid receptor 2 or 4 in subcutaneous adipose tissue of patients with newly diagnosed type 2 diabetes mellitus. Nutr Diabetes, 2018; 8:49.
32.
LafontanM, LanginD: Lipolysis and lipid mobilization in human adipose tissue. Prog Lipid Res, 2009; 48:275–297.
33.
FruhbeckG, Mendez-GimenezL, Fernandez-FormosoJA, FernandezS, RodriguezA: Regulation of adipocyte lipolysis. Nutr Res Rev, 2014; 27:63–93.
34.
SchweigerM, SchreiberR, HaemmerleG, et al.: Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem, 2006; 281:40236–40241.
35.
BickelPE, TanseyJT, WelteMA: PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores. Biochim Biophys Acta, 2009; 1791:419–440.
36.
Bolsoni-LopesA, Alonso-ValeMI: Lipolysis and lipases in white adipose tissue—An update. Arch Endocrinol Metab, 2015; 59:335–342.
37.
KonigeM, WangH, SztalrydC: Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis. Biochim Biophys Acta, 2014; 1842:393–401.
38.
LonnqvistF, ThomeA, NilsellK, HoffstedtJ, ArnerP: A pathogenic role of visceral fat beta 3-adrenoceptors in obesity. J Clin Invest, 1995; 95:1109–1116.
39.
WarnerA, KjellstedtA, CarrerasA, et al.: Activation of beta3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats. Am J Physiol Endocrinol Metab, 2016; 311:E901–E910.
40.
EllisJM, LiLO, WuPC, et al.: Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis. Cell Metab, 2010; 12:53–64.
41.
CedikovaM, KripnerovaM, DvorakovaJ, et al.: Mitochondria in white, brown, and beige adipocytes. Stem Cells Int, 2016; 2016:6067349.
42.
ShenW, WangY, LuSF, et al.: Acupuncture promotes white adipose tissue browning by inducing UCP1 expression on DIO mice. BMC Complement Altern Med, 2014; 14:501.
43.
CariouB, CharbonnelB, StaelsB: Thiazolidinediones and PPARgamma agonists: Time for a reassessment. Trends Endocrinol Metab, 2012; 23:205–215.
44.
SchneebergerM, EverardA, Gomez-ValadesAG, et al.: Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep, 2015; 5:16643.
45.
HeM, PeiZ, MohsenAW, et al.: Identification and characterization of new long chain acyl-CoA dehydrogenases. Mol Genet Metab, 2011; 102:418–429.
46.
QianSW, TangY, LiX, et al.: BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci U S A, 2013; 110:E798–E807.
47.
SharmaA, HuardC, VernochetC, et al.: Brown fat determination and development from muscle precursor cells by novel action of bone morphogenetic protein 6. PLoS One, 2014; 9:e92608.
48.
NelsonCN, ListEO, IeremiaM, et al.: Growth hormone activated STAT5 is required for induction of beige fat in vivo. Growth Horm IGF Res, 2018; 42–43:40–51.
49.
BartesaghiS, HallenS, HuangL, et al.: Thermogenic activity of UCP1 in human white fat-derived beige adipocytes. Mol Endocrinol, 2015; 29:130–139.
50.
Torrens-MasM, OliverJ, RocaP, Sastre-SerraJ: SIRT3: Oncogene and tumor suppressor in cancer. Cancers (Basel), 2017; 9:E90.
51.
SunK, KusminskiCM, Luby-PhelpsK, et al.: Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol Metab, 2014; 3:474–483.
52.
RafiiS, CarmelietP: VEGF-B improves metabolic health through vascular pruning of fat. Cell Metab, 2016; 23:571–573.
53.
HilseKE, KalinovichAV, RupprechtA, et al.: The expression of UCP3 directly correlates to UCP1 abundance in brown adipose tissue. Biochim Biophys Acta, 2016; 1857:72–78.
54.
ChenY, ChenPD, BaoBH, et al.: Anti-thrombotic and pro-angiogenic effects of Rubia cordifolia extract in zebrafish. J Ethnopharmacol, 2018; 219:152–160.
55.
HondaresE, IglesiasR, GiraltA, et al.: Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem, 2011; 286:12983–12990.
56.
MaurerSF, FrommeT, GrossmanLI, HuttemannM, KlingensporM: The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice. Sci Rep, 2015; 5:17704.
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