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, 9 (7), e103093
eCollection

Capsaicin Induces "Brite" Phenotype in Differentiating 3T3-L1 Preadipocytes

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Capsaicin Induces "Brite" Phenotype in Differentiating 3T3-L1 Preadipocytes

Ritesh K Baboota et al. PLoS One.

Abstract

Objective: Targeting the energy storing white adipose tissue (WAT) by pharmacological and dietary means in order to promote its conversion to energy expending "brite" cell type holds promise as an anti-obesity approach. Present study was designed to investigate/revisit the effect of capsaicin on adipogenic differentiation with special reference to induction of "brite" phenotype during differentiation of 3T3-L1 preadipocytes.

Methods: Multiple techniques such as Ca2+ influx assay, Oil Red-O staining, nutrigenomic analysis in preadipocytes and matured adipocytes have been employed to understand the effect of capsaicin at different doses. In addition to in-vitro experiments, in-vivo studies were carried out in high-fat diet (HFD) fed rats treated with resiniferatoxin (RTX) (a TRPV1 agonist) and in mice administered capsaicin.

Results: TRPV1 channels are expressed in preadipocytes but not in adipocytes. In preadipocytes, both capsaicin and RTX stimulate Ca2+ influx in dose-dependent manner. This stimulation may be prevented by capsazepine, a TRPV1 antagonist. At lower doses, capsaicin inhibits lipid accumulation and stimulates TRPV1 gene expression, while at higher doses it enhances accumulation of lipids and suppresses expression of its receptor. In doses of 0.1-100 µM, capsaicin promotes expression of major pro-adipogenic factor PPARγ and some of its downstream targets. In concentrations of 1 µM, capsaicin up-regulates anti-adipogenic genes. Low-dose capsaicin treatment of 3T3-L1 preadipocytes differentiating into adipocytes results in increased expression of brown fat cell marker genes. In white adipose of mice, capsaicin administration leads to increase in browning-specific genes. Global TRPV1 ablation (i.p. by RTX administration) leads to increase in locomotor activity with no change in body weight.

Conclusion: Our findings suggest the dual modulatory role of capsaicin in adipogenesis. Capsaicin inhibits adipogenesis in 3T3-L1 via TRPV1 activation and induces brown-like phenotype whereas higher doses.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Effect of capsaicin and capsazepine on adipogenesis in 3T3-L1 cells.
(A) Cell viability in pre-adipocytes treated with capsaicin for 72 hrs; (B) Effect of capsaicin, capsazepine and RTX on differentiation of 3T3-L1 cells. Black spots in images represents area stained by ORO dye; (C&D) Effect of capsaicin and capsazepine on lipid accumulation in 3T3-L1 adipocytes. All values are expressed as mean ± S.E.M. (n = 3). One way ANOVA followed by Tukey's multiple comparison post hoc test was applied. *P<0.05 as compared to control. ORO =  Oil red O, RTX =  resiniferatoxin.
Figure 2
Figure 2. Effect of capsaicin on TRP expression and Ca2+ influx in 3T3-L1 cells.
(A) Normalized mRNA expression levels of TRPV1, TRPV4, TRPC1 and TRPC5 in 3T3-L1 cells differentiated for 8 days; (B) Change in TRPV1 expression levels in adipocyte when differentiated in presence of capsaicin. (C & D) Effect of TRPV1 agonist, Cap and RTX, and antagonist, Cpz, on Ca2+ influx in pre-adipocytes. All values are expressed as mean ± S.E.M. (n = 3). *P<0.05 as compared to control or pre-adipocyte (wherever mentioned in panel), P<0.05 as compared to adipocyte. TRPV =  transient receptor potential channel vanaloid type, TRPC =  transient receptor potential channel canonical type, Cap =  Capsaicin, RTX =  resiniferatoxin, Cpz =  Capsazepine.
Figure 3
Figure 3. Effect of capsaicin on the expression of PPARγ and its downstream target genes.
Data are expressed as mean ±S.E.M. (n = 3). *P<0.05 as compared to pre-adipocytes, P<0.05 as compared to adipocytes. PA =  Pre-adipocyte, A =  Adipocyte.
Figure 4
Figure 4. Effect of capsaicin on the expression of anti-adipogenesis genes during 3T3-L1 preadipocyte differentiation into adipocytes.
Data are expressed as mean ± S.E.M., (n = 3). *P<0.05 as compared to pre-adipocytes, P<0.05 as compared to adipocytes.
Figure 5
Figure 5. Effect of capsaicin on brown adipocyte specific genes in 3T3-L1 adipocytes.
Data are shown mean ± S.E.M., (n = 3). *P<0.05 as compared to adipocytes, P<0.05 as compared to capsaicin (1 µM).
Figure 6
Figure 6. Effect of co-administration of capsaicin and capsazepine on PPAR γ, adipogenesis modulating genes and brown adipocyte specific genes in 3T3-L1 adipocytes.
All values are presented as mean ± S.E.M. (n = 3). *P<0.05 as compared to adipocyte, P<0.05 as compared to capsaicin (1 µM).
Figure 7
Figure 7. Effect of capsaicin on the release of inflammatory mediators during 3T3-L1 preadipocyte differentiation into adipocytes.
All values are presented as mean ± S.E.M. (n = 3). *P<0.05 as compared to pre-adipocytes, P<0.05 as compared to adipocytes.
Figure 8
Figure 8. Effect of TRPV1 ablation on: (A) Average body weight gain after 4 weeks, (B) pain threshold and (C) locomoter activity (in photoactometer) after one week.
(D) Effect of capsaicin on brown adipocyte specific genes in sWAT. All values are expressed as mean ± S.E.M., (n = 5). *P<0.05 as compared to control.

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Grant support

The authors would like to thank Department of Biotechnology, Government of India, for research grants given to National Agri-Food Biotechnology Institute (NABI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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