Zc3h10 regulates adipogenesis by controlling translation and F-actin/mitochondria interaction

Abstract

The commitment of mesenchymal stem cells to preadipocytes is stimulated by hormonal induction. Preadipocytes induced to differentiate repress protein synthesis, remodel their cytoskeleton, and increase mitochondrial function to support anabolic pathways. These changes enable differentiation into mature adipocytes. Our understanding of the factors that coordinately regulate the early events of adipocyte differentiation remains incomplete. Here, by using multipronged approaches, we have identified zinc finger CCCH-type containing 10 (Zc3h10) as a critical regulator of the early stages of adipogenesis. Zc3h10 depletion in preadipocytes resulted in increased protein translation and impaired filamentous (F)-actin remodeling, with the latter detrimental effect leading to mitochondrial and metabolic dysfunction. These defects negatively affected differentiation to mature adipocytes. In contrast, Zc3h10 overexpression yielded mature adipocytes with remarkably increased lipid droplet size. Overall, our study establishes Zc3h10 as a fundamental proadipogenic transcription factor that represses protein synthesis and promotes F-actin/mitochondria dynamics to ensure proper energy metabolism and favor lipid accumulation.

MYH10 governs adipocyte function and adipogenesis through its interaction with GLUT4

“…The cytoskeleton is vital for determining and maintaining the shape and function of adipocytes, and depolymerization and repolymerization of actin affect both early adipogenesis and terminal differentiation 7,58 . Notably, reorganization of other cytoskeletal components has been shown to affect lipogenesis, mitochondrial activity, and glucose uptake in adipocytes [13][14][15]62,63 . MYH10 filaments were shown to undergo reorganization in a similar fashion to actin filaments 6 , with a stress-fiber-like appearance in preadipocytes, in contrast to the cortical distribution seen in differentiated cells.…”

Regulatory mechanisms of the early phase of white adipocyte differentiation: an overview

“…More in-depth, proliferating mesenchymal stem cells (MSCs) show several F-actin stress fibers throughout the cell body. Upon addition of the adipogenic cocktail, F-actin moves toward the cell’s periphery, which begins to change its shape to a spherical appearance [ 72 ]. Factors that can regulate this process also have an impact on adipocyte differentiation.…”

“…An opposite situation appears when Zc3h10 is overexpressed. Zc3h10 overexpression enhances F-actin reorganization toward the cell periphery and stimulates lipid droplets formation [ 72 ]. In addition, it has been observed that actin organization also plays a key role in determining a discrete subpopulation of functional mitochondria, a key step towards mature adipocyte formation [ 72 ].…”

“…Its overexpression before adipogenesis induction results in decreased expression of key adipogenic genes and reduced lipid accumulation [ 69 ] ROCK1 It is a major downstream effecter of RhoA and is a regulator of the actomyosin cytoskeleton. It is negatively associated with adipocyte differentiation, and the inhibition of this pathway promotes adipogenesis in vitro [ 70 ] Zc3h10 A transcription factor involved in the control of energy metabolism and mitochondrial function; its downregulation impairs F-actin cytoskeleton reorganization during the early adipogenesis [ 72 ] DPYSL2/CRMP2 It is known to be present as a full and a small isoform. The small isoform is higher at the day of differentiation induction and then decreases.…”

“…Notably, adipose tissue stem cell transition to preadipocytes is not associated to significant morphological changes, rather to biochemical, genetic, and metabolic rearrangements; these include F-actin fibers breakdown and F-actin rearrangement to preadipocyte periphery (step 3), mitochondrial biogenesis and fusion associated to increased metabolic performance (step 4), and epigenetic events occurring on both DNA, histones and RNA (step 5). Among the main epigenetic modification, histone phosphorylation, acetylation, methylation and ubiquitination together with DNA and RNA methylation have been demonstrated as important regulatory steps of adipogenesis [ 72 , 120 , 121 ] …”