Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 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
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Secondly we have demonstrated that BCAA increased adipocyte

    2018-10-23

    Secondly, we have demonstrated that BCAA increased adipocyte lipolysis and FFA release via AMPKα2-dependent HSL activation. Lipolysis rates are precisely regulated through hormonal and biochemical signals. Initiation of TG hydrolysis in adipose tissue is controlled by two enzymes, HSL and ATGL (also known as desnutrin). HSL hydrolyses triglycerides, diglycerides, and cholesteryl esters, although with much greater specificity for diacylglycerol (DG). Lipolytic agents (such as β-adrenergic agonists) acutely regulate HSL by increasing cellular cyclic adenosine monophosphate (cAMP) levels, thus activating cAMP-dependent protein kinase (protein kinase A, PKA). PKA phosphorylates HSL at serine563, serine659, and serine660, thereby increasing its intrinsic activity. PKA also promotes HSL translocation from cytosol to the lipid droplet (Yeaman, 2004). Activation of phosphodiesterase (PDE) reduces cAMP levels, with consequent reduced PKA activity, inhibiting HSL phosphorylation and translocation. In bombesin receptor to HSL, the activity of ATGL is specific for TG and has limited activity against DG. Our current study demonstrated BCAA supplementation had no significant effect on ATGL expression. However, BCAA supplementation significantly reduced PDE activity and increased HSL phosphorylation without altering its expression. These results suggest BCAA increases adipocyte lipolysis likely via attenuating PDE-inhibition of HSL. AMPK is a crucial sensor of redox status and energy balance. Its role in lipolysis is controversial. Initial evidence of a regulatory role for AMPK in adipocyte lipolysis originated from the in vitro observation that HSL is phosphorylated by AMPK at serine565. Phosphorylation at serine565 blocks the phosphorylation of HSL by PKA at serine563, 659, 660 (Yeaman, 2004). Based upon these in vitro studies, it was proposed AMPK activation would exert an anti-lipolytic effect in adipocytes. However, several recent studies have demonstrated AMPK activation promotes lipolysis (Yin et al., 2003; Koh et al., 2007), supported by evidence acute and chronic exercise increase catecholamine release, lipolysis, and AMPK activation in the adipose tissue (Koh et al., 2007). An anti-lipolytic role for AMPK appears counterintuitive because during exercise, circulating levels of FFA are increased significantly. Such contradictory results may be explained by the opposite regulatory effects exerted by different AMPK isoforms. Specifically, adipocytes from AMPKα1-knockout mice exhibit increased lipolysis, indicating an anti-lipolytic role of this enzyme (Daval et al., 2005). In contrast, mice lacking the AMPKα2 subunit manifest increased adiposity and weight gain (Villena et al., 2004), suggesting a pro-lipolytic role of this subunit. More importantly, a recent study demonstrated nicotine-induced lipolysis is lost in AMPKα2, but not AMPKα1, knockout adipocytes, further supporting the role of AMPKα2 in promoting lipolysis (Wu et al., 2015). To this end, our current study demonstrated BCAA significantly increased adipocyte lipolysis, an effect blocked by AMPKα2, not AMPKα1, knockdown. However, the detailed molecular signaling by which BCAA inhibits PDE activity via AMPKα2 remains unidentified. Moreover, whether BCAA-induced HSL phosphorylation is a direct result of AMPKα2, or an indirect effect via PDE inhibition, was not directly addressed in this study. These important questions warrant additional ongoing investigation, underway in our laboratory. Thirdly, we have provided the direct evidence that BCAA supplementation atop HFD caused significant liver damage via two mTOR-activated signaling pathways: inhibition of hepatic lipogenesis and blockage of autophagy. De novo hepatic lipogenesis is regulated by a group of genes controlled by SREBP-1c, the master regulator of the hepatic lipogenic program, regarded as a therapeutic target against hepatic lipogenesis and its resultant metabolic disorders (Postic and Girard, 2008). Our current study demonstrated BCAA supplementation significantly inhibited hepatic SREBP-1c expression and reduced lipogenesis enzyme expression in an mTOR-dependent manner. However, mTOR blockade with rapamycin significantly attenuated, not exacerbated, BCAA-induced liver injury. These results suggest the beneficial effect of mTOR-mediated global inhibition of hepatic lipogenesis by BCAA is overwhelmed by stronger deleterious signaling pathways concurrently activated by mTOR.