14-3-3ζ coordinates adipogenesis of visceral fat

Abstract

The proteins that coordinate complex adipogenic transcriptional networks are poorly understood. 14-3-3ζ is a molecular adaptor protein that regulates insulin signalling and transcription factor networks. Here we report that 14-3-3ζ-knockout mice are strikingly lean from birth with specific reductions in visceral fat depots. Conversely, transgenic 14-3-3ζ overexpression potentiates obesity, without exacerbating metabolic complications. Only the 14-3-3ζ isoform is essential for adipogenesis based on isoform-specific RNAi. Mechanistic studies show that 14-3-3ζ depletion promotes autophagy-dependent degradation of C/EBP-δ, preventing induction of the master adipogenic factors, Pparγ and C/EBP-α. Transcriptomic data indicate that 14-3-3ζ acts upstream of hedgehog signalling-dependent upregulation of Cdkn1b/p27Kip1. Indeed, concomitant knockdown of p27Kip1 or Gli3 rescues the early block in adipogenesis induced by 14-3-3ζ knockdown in vitro. Adipocyte precursors in 14-3-3ζKO embryos also appear to have greater Gli3 and p27Kip1 abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3ζ is a critical upstream driver of adipogenesis.

Upregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression

“…LDHA is known to be regulated by other oncogenes such as HIF-1a during cancer progression, thus cancer cells have expanded regulatory mechanism to confer metabolic advantages in the advanced stages of diseases. Previous studies showed that 14-3-3ζ is involved in multiple functions including chemoresistance, epigenetics regulation, adipogenesis and metastasis [11, 33–35]. Here, we demonstrated a novel role of 14-3-3ζ in cancer cell metabolism and our findings bring new insights into the mechanistic understanding of 14-3-3ζ overexpression-mediated breast cancer initiation and progression of early-stage breast diseases.…”

14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

“…This is a plausible scenario because proinflammatory cytokines can also affect other biological processes that control Akt function such as protein synthesis 2 and/or Akt targeting/shuttling, 2 which is known to be important for controlling Akt destiny and function. 39 14-3-3ζ stimulates PI3K signaling 59 and also activates PDK1, thus its presence could be important but not essential 60 to induce Akt activation, those properties in 14-3-3ζ could explain in part the tumor-promoting function attributed to 14-3-3ζ upregulation. 61 Additionally, the ratio maintained between the dimeric and monomeric forms of 14-3-3ζ might have a role in controlling Akt activity; and it is possible that oscillations in the amount of p14-3-3ζS58 are necessary not only to maintain the Akt signal but also to control its cellular localization, which is important because Akt phosphorylates at least 100 non-redundant substrates in different cell compartments.…”

A causal role for hyperinsulinemia in obesity

“…The expansion of white adipose tissue (WAT) that defines obesity can occur through both adipocyte hypertrophy (lipid filling) and hyperplasia (adipogenesis or increased differentiation of adipocyte precursor cells into adipocytes), but the mechanisms controlling these processes have not yet been fully delineated (Berry et al 2014, Lim et al 2015. Biochemical studies have shown that insulin plays key roles in regulating white adipocyte lipid accumulation, by inhibiting lipolysis as well as promoting fatty acid uptake and triglyceride synthesis (lipogenesis) and also by stimulating the expression of genes involved in lipid uptake and storage (Kersten 2001, Czech et al 2013 (Fig.…”

“…2). Over a longer term, insulin signaling can drive adipogenesis, an orchestrated progression of events involving transient expression of the transcription factors CCAAT/enhancer-binding protein (C/EBP) β and C/EBPδ leading to induction of the master adipogenic regulators C/EBPα and peroxisome proliferator-activated receptor (PPAR) γ (Cook & Cowan 2008, Berry et al 2014, Lim et al 2015. Recently, it has also been shown that hyperinsulinemia promotes adipose tissue inflammation in mice, which contributes to disruption of metabolic processes such as de novo lipogenesis in WAT .…”

“…WAT is the primary type of adipose tissue that serves as an energy reserve, and WAT also secretes an array of factors with autocrine, paracrine and endocrine functions (Berry et al 2014). Subcutaneous and visceral depots of WAT have distinct characteristics, differing in cellular composition, innervation, metabolic characteristics and secretory profile; in general, visceral WAT is more implicated in perpetuating metabolic dysfunction, compared to subcutaneous WAT (Lee et al 2013, Lim et al 2015. Interestingly, insulin treatment may have selective trophic effects on subcutaneous WAT when compared with visceral WAT in a rat model of latestage type 2 diabetes (Skovso et al 2015).…”