Results of this study are demonstrated distinctive effects and potential mechanism
of NaB on adipocyte differentiation in three in vitro models, mouse and porcine SVCs,
and mouse 3T3-L1 cells. NaB inhibited lipid accumulation of cells (Figure 1) and
expression of adipogenic marker Adipoq, Glut4, Fabp4, Fasn, Srebf1 and Cebpβ
mRNAs (Figure 5; Figure 6C; Figure 7A) differentiating mouse SVCs. Inversely, we
also showed that NaB stimulated lipid accumulation in porcine SVCs (Figure 3), with
up-regulation of FASN, LPL, PPARγ, CEBPα, and SREBF1 (Figure 10C and D; Figure
11). However, NaB failed to influence adipocyte differentiation in mouse 3T3-L1 cells
(Figure 2; Figure 8; Figure 9). These results indicate that NaB effects on adipogenesis
depend on species and cell models. NaB induced adipocyte differentiation in porcine
SVCs agrees with studies revealing a promotional function of SCFAs in adipocyte
differentiation of porcine adipocytes (Li et al., 2014). Unexpectedly, NaB showed no
obvious effects on adipogenesis of 3T3-L1 cells, it is differ from other studies that
SCFAs stimulate 3T3-L1 cells to differentiate into mature adipocytes (Haberland et al.,
2010; Hong et al., 2005; Yoo et al., 2006). No effects of SCFAs on adipogenetic
program of human SVCs (Chatterjee et al., 2011). Nonetheless, NaB was shown to
inhibit the differentiation of human mesenchymal stem cells into mature adipose cells
(Chen et al., 2007). The reasons that SCFAs affect adipocyte differentiation with
seemingly incompatible functions are still unknown, but we speculate that these causes
may be due to the diverse status among different research groups, such as the use of
distinct species, cell models and different experimental operations in cell culture system.
On the other hand, we reported the dissimilarity between mouse SVCs primary culture
and 3T3-L1 cell line. It is important to point out that even if cells are derived from the
same species, different cell types may have distinctive response.
Butyrate is known to bind to FFAR2 and FFAR3 (Bindels et al., 2013). In addition,
butyrate also have HDAC inhibitory activity (de Ruijter et al., 2003). Several prior
studies have demonstrated that SCFAs modulate differentiation of pradipocytes by
activating FFAR2 or inhibiting HDAC. Hong et al. found that the expression amount of
Ffar2 mRNA was high in mouse adipose tissues, but the level of Ffar3 was not detected.
Additionally, Ffar2 can be detected after differentiating for 3 days in 3T3-L1 cells
(Hong et al., 2005). Frost and colleagues also exhibited expression of Ffar2 over 2 days
following onset of differentiation in 3T3-L1 cells (Frost et al., 2014). Neither FFAR2
nor FFAR3 were detected in porcine SVCs before or during adipogenesis (Li et al.,
2014). Nonetheless, both HDAC family mRNA or protein expression level can be
detected in preadipocytes and mature adipocytes in porcine SVCs, 3T3-L1 cells and
other species (Chatterjee et al., 2011; Li et al., 2014; Yoo et al., 2006). Therefore we
hypothesized that the discrepant observations of NaB effects may be due to the distinct
mechanisms of NaB via different receptor in various species. For example FFAR2 and
FFAR3 are not expressed in porcine adipose tissue, they would not have any role in
mediating NaB effect in pig. Moreover, FFAR3 mRNA is absent in mouse adipose
tissues and undifferentiated or differentiated 3T3-L1 cells. We tested whether 4-CMTB,
a specific agonist of FFAR2 which suppresses the mouse SVCs adipogenesis. Mouse
SVCs treated with 4-CMTB for 9 days during differentiation showed a remarkable
inhibition of lipid droplet accumulation, and low Adipoq, Fabp4, and Cebpα gene
expression (Figure 12; Figure 13A and B; Figure 14B). To rule out that the depressing
situation is due to the toxicity of drugs used, we initially tested pharmacological dosage,
and observed that mouse SVCs cultured with 100 μM for 1 day started to detach from
the surface of culture dishes. To avoid this detachment, the highest concentration of
4-CMTB was used as 10 μM, but there was no direct evidence that NaB restrains
adipogenic markers expression as well as fat accumulation. These results suggest that
FFAR2 and its agonists function as regulators of adipocyte differentiation in mouse
SVCs.
In addition to butyrate, there are lots of compounds affecting adipogenesis. Huang
et al. suggested that cinnamaldehyde (CA), the major component of cinnamon used in
naturopathic medicine, exerts antiadipogenic effects in 3T3-L1 cells (Huang et al.,
2011). Resveratrol (Res), a natural polyphenolic compound, can inhibit adipocyte
differentiation and lipogenesis in 3T3-L1 adipocytes (Chen et al., 2011). Other natural products such as dioxinodehydroeckol (DHE), obtained from marine seaweeds also has
an effect to inhibit 3T3-L1 pradipocytes differentiation into mature adipocytes (Kim and
Kong, 2010). The commonality CA, Res and DHE all diminish adiposity via
phosphorylating AMPK. AMPK is a key player in several aspects of energy
homeostasis, such as regulating glucose transport, lipolysis or lipogenesis (Daval et al.,
2006). Furthermore, AMPK is associated with adipogenesis of 3T3-L1 cells, as
indicated by the observations that
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), a pharmacological
activator of AMPK, suppresses expression of adipocyte-specific transcription factors,
including Pparγ, Cebpα and Srebf1 (Giri et al., 2006; Habinowski and Witters, 2001).
We speculated that NaB and Ffar2 may inhibit adipocyte differentiation in mouse SVCs
through AMPK pathway. We found neither NaB treated group nor 4-CMTB treated
group showed a significant change of AMPK phosphorylation (Figure 15). These results
failed to support our hypothesis that NaB has antiadipogenic effect in mouse SVCs
through AMPK.
In conclusion, our results showed that NaB, indeed, plays an important role in
regulating adipogenesis. Based on our findings, NaB inhibits the adipocyte
differentiation of mouse SVCs, but has no effect on mouse 3T3-L1 cells. However, NaB
stimulates the adiposity in porcine SVCs. Furthermore, we also suggested that Ffar2
downregulates the adiposity of mouse SVCs. Although the precise pathways by which
NaB induces antiadipogenesis of mouse SVCs remains to be determined, our results
might be might be a role of NaB in modifying adipocyte differentiation.
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