• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • Previously we reported that the inhibition of PKC


    Previously, we reported that the inhibition of PKC-ζ and PKC-ε activity in hypertrophic adipocytes had deleterious effects on EPA-induced GPR120-mediated VEGF-A production [12]. However, the activation of PKC-θ, -ζ and -λ can also enhance the phosphorylation of IKK and p65, and facilitate the translocation of p50/p105 and p65 to the nucleus activating their downstream inflammatory pathway [14]. Therefore, the inactivation of PKCs (i.e. PKC-δ and -ε) might improve obesity-induced metabolic disorders by attenuating pro-inflammatory effects in adipocytes [15]. Findings from our current study suggest that PKC activity in adipocytes is pro-inflammatory (IL-6 and CCL2), and might impair mitochondrial activity (for PGC1α) (Fig. 3). These observations are in accord with reports demonstrating that PKC has pro-inflammatory effects [14], [15]. Nevertheless, the activation/inhibition of different isoforms of PKC produces different biological effects in terms of inflammation (PKC-α and -ε induce inflammation) and proliferation (PKC-δ reduces proliferation) as reported for Jurkat T-cells [16]. Therefore, further studies are required to elucidate the involvement of different isoforms of PKC with the anti-inflammatory effects of GPR120 activation in adipocytes. Studies have shown that in obesity, pro-inflammatory cytokines such as CCL2 dysregulate the production of ECM-modulating factors in macrophages and other immune butein [10], [17] and presumably induce the migration of immune cells into atherosclerotic plaques and possibly other tissues [18]. We found that RAW 264.7 cells grown in conditioned medium collected from adipocytes dramatically enhanced the mRNA levels of MMP3 and TIMP1, and significantly enhanced MMP9 mRNA levels (Fig. 4A–C). These high mRNA levels were attenuated by conditioned medium collected from GSK137647-treated adipocytes. Moreover, the IKKβ inhibitor, Bay 11-7082, blocked the increase in mRNA levels of these ECM remodeling factors. Consistently, conditioned medium collected from GSK137647-treated adipocytes significantly blocked the LPS-induced migration of macrophages (Fig. 4E and F). Of note, despite the significant upregulation of ECM remodeling factors, conditioned medium alone did not influence macrophage migration, rather LPS was required to initiate the process (Fig. 4E and F). We assume that the TLR4 pathway is required for the initiation of macrophage migration. Furthermore, TLR4 activity considerably predisposes individuals to obesity [19]. Therefore, our findings provide compelling evidence that pro-inflammatory adipocytokines released from adipocytes influence ECM production and enhance macrophage migration. Moreover, this migration is attenuated by the paracrine activation of GPR120 in adipocytes. Although obesity was previously shown to enhance the production of pro-inflammatory adipocytokines and have an effect on macrophage infiltration, the contribution of nutritional receptors in this process is still poorly understood. Here, we demonstrate that GPR120 plays a differential role in adipocytes. While GPR120-mediated PKC activation is pro-inflammatory, that of NF-κB inactivation is anti-inflammatory. Despite this counteractive mechanism, the overall activation of GPR120 attenuates the production of pro-inflammatory adipocytokines. This anti-inflammatory milieu contributes to reduce the production of ECM remodeling factors from macrophages in a paracrine manner and protects adipocytes from macrophage infiltration. However, rigorous studies are required to investigate the extent of GPR120 activation using novel compounds to ameliorate obesity-induced metabolic disorders [9].
    Funding This work was partially supported by a grant-in-aid from the Japanese Ministry of Sports and Culture Nos. 20500422 and 24591057, awarded to K. Ohmori.
    Disclosure summary
    Introduction White adipose tissue (WAT), which is considered as the main reservoir to store energy, plays an important role as an endocrine organ in glucose metabolism and immune functions by secreting a vast range of regulatory factors (Kershaw and Flier, 2004). Given the vital role of WAT in the health implications and energy homeostasis, it is essential to investigate the molecular mechanisms of adipogenesis. Until now, a variety of transcription factors, including CCAAT enhancer binding protein α (C/EBPα), C/EBPβ, C/EBPδ and peroxisome proliferator activated receptor γ (PPARγ), have been demonstrated to be involved in this process (Otto and Lane, 2005, Tang and Lane, 2012). Among them, PPARγ is considered as the master regulator of the complex transcriptional cascade in adipogenic differentiation and the terminal differentiation does not occur without PPARγ (Cristancho and Lazar, 2011, Rosen et al., 1999).