Mark4 Inhibited the Browning of White Adipose Tissue by Promoting Adipocytes Autophagy in Mice

Abstract

Autophagy can remove excess or dysfunctional proteins and organelles to maintain cellular homeostasis. Browning of white adipose tissue increases the energy expenditure. Microtubules affinity regulated kinase 4 (Mark4) can regulate a variety of physiological processes. According to previous studies, we speculated that Mark4-autophagy-browning of white adipose tissue had certain linkages. Here, we established two autophagy models through serum starvation and rapamycin treatment and detected that the overexpression of Mark4 increased the expression of autophagy-related factors Beclin1, ATG7, and significantly decreased the autophagy substrate P62. Further tests showed that the overexpression of Mark4 promoted the conversion of autophagy marker protein LC3A to LC3B-II by activating the AMP-activated protein kinase (AMPK) pathway and inhibition of the AKT/mTOR signaling. Moreover, Mark4 decreased the expression of thermogenesis genes via promoting autophagy. These results indicated that Mark4 inhibited the browning of white adipose tissue via promoting autophagy. AMPK signaling pathway. By adding compound C, the phosphorylation of AMPK and the formation of LC3B-II were reduced while the level of autophagy substrate p62 was increased ( Figure 4A,B). The results of AKT pathway examination was opposite. The overexpression of Mark4 significantly inhibited the phosphorylation of AKT and mTOR, accompanied by an increase in LC3B-II and a decrease in P62. After treating with the AKT inhibitor MK2206, the phosphorylation levels of AKT, mTOR, and the protein level of P62 were significantly reduced. The LC3B-II expression was increased ( Figure 4C,D). These results indicated that Mark4 could regulate serum starvation-induced autophagy via the AMPK/AKT signal pathway.

Amidation-Modified Apelin-13 Regulates PPARγ and Perilipin to Inhibit Adipogenic Differentiation and Promote Lipolysis

“…It is one of the most important target tissues for obesity treatment. The cause of obesity may also be due to the production and pathological secretion of adipokines in adipose tissue, and it plays a role in the development of obesity-related diseases [ 16 ]. Apelin is one of these adipokines.…”

Non-shivering Thermogenesis Signalling Regulation and Potential Therapeutic Applications of Brown Adipose Tissue

“…Recent studies have found that NP-cGMP signalling can also activate mTORC1 through PKG, thereby inducing adipose browning 63 . Many recent studies have found that certain regulatory factors, including SNS, T3, and Mark4, can affect autophagy by regulating mTOR, ultimately regulating thermogenesis 64 - 66 .…”

Microtubule affinity regulating kinase 4: A promising target in the pathogenesis of atherosclerosis

“…White adipocyte browning reduces adverse effects of white adipose tissue and protects against obesity, which may be a novel therapeutic target for atherosclerosis (Lo & Sun, 2013). Yang and colleagues (2020) reported that overexpression of MARK4 significantly inhibits browning of white adipose tissue by decreasing the expression of thermogenesis genes UCP1, PGC1α, Prd16, and Cideα. Thus, these findings suggest that MARK4 may promote the development of atherosclerosis via inhibiting the browning of white adipose tissue.…”

“…The major biological function of MARK4 is to phosphorylate the microtubule‐associated proteins, thereby increasing the dynamics of microtubule and promoting cell division, cell shape alterations, cell cycle control, and cell polarity determination (Annadurai et al, 2017; Naz et al, 2013). However, increasing evidence reveals that MARK4 has a variety of potential biological functions, including affecting lipid metabolism, inflammation, insulin signaling, and glucose homeostasis, white adipocyte browning, and oxidative stress (Z. Liu et al, 2016; C. Sun et al, 2012; Tian et al, 2019; Yang et al, 2020). Moreover, the expression of MARK4 is significantly increased in human atherosclerotic lesions compared with adjacent areas (Clement et al, 2019).…”

“…Liu et al, 2016;C. Sun et al, 2012;Tian et al, 2019;Yang et al, 2020). Moreover, the expression of MARK4 is significantly increased in human atherosclerotic lesions compared with adjacent areas (Clement et al, 2019).…”