Nck2, an unexpected regulator of adipogenesis

Abstract

The regulation of adipose tissue expansion by adipocyte hypertrophy and/or hyperplasia is the topic of extensive investigations given the potential differential contribution of the 2 processes to the development of numerous chronic diseases associated with obesity. We recently discovered that the loss-of-function of the Src homology domain-containing protein Nck2 in mice promotes adiposity accompanied with adipocyte hypertrophy and impaired function, and enhanced adipocyte differentiation in vitro. Moreover, in severely-obese human's adipose tissue, we found that Nck2 expression is markedly downregulated. In this commentary, our goal is to expand upon additional findings providing further evidence for a unique Nck2-dependent mechanism regulating adipogenesis. We propose that Nck2 should be further investigated as a regulator of the reliance of white adipose tissue on hyperplasia versus hypertrophy during adipose tissue expansion, and hence, as a potential novel molecular target in obesity.

Nck1 Deficiency Impairs Adipogenesis by Activation of PDGFRα in Preadipocytes

“…In this perspective, our studies on the role of Nck adaptor proteins in WAT development reveal that both Ncks regulate adipogenesis, but in an opposite manner and at different stages during this process. Nck2 is involved in regulating the transition of preadipocyte into adipocyte by regulating PERK activation and signaling ( Dusseault et al., 2016 , Haider et al., 2017 ), whereas our findings reveal that Nck1 controls preadipocyte commitment by modulating PDGFRα activation and signaling, and is required to maintain an adequate number of adipocyte precursor cells in WAT. Analysis of Nck1 and Nck2 interactome profiles in the preadipocyte and adipocyte might provide an understanding of how these two highly identical adaptor proteins differentially regulate WAT homeostasis.…”

“…In this perspective, our work addressing the role of both Ncks in WAT unveils insights on mechanisms regulating adipogenesis. Indeed, we have previously demonstrated that Nck2 limits adiposity in mice and adipocyte differentiation in vitro ( Dusseault et al., 2016 , Haider et al., 2017 ). Mechanistically, we provided evidence that Nck2 regulates adipogenesis by controlling activation of PERK during preadipocyte to adipocyte transition.…”

“…Our group has been at the forefront in unraveling the role of the Src homology (SH) domain-containing adaptor protein Nck2 (non-catalytic region of receptor tyrosine kinase 2) as a key player in limiting adipogenesis and adiposity, and regulating adipocyte function in mice ( Dusseault et al., 2016 , Haider et al., 2017 ). In agreement, we found that Nck2 downregulation in human visceral WAT correlates with severe obesity ( Dusseault et al., 2016 ).…”

20 Years with SGBS cells - a versatile in vitro model of human adipocyte biology

“…SGBS cells have been used to understand basic principles of adipogenesis, e.g., by comparing transcription factor usage in human and rodent cells [13], or by investigating the effect of radiation [15] or compressive force on human preadipocytes [16]. Using gain-and loss-of-function experiments, the effects of different [17][18][19][20] regulators of adipogenesis have been addressed. Recent literature demonstrates that microRNAs play a pivotal role in adipogenesis.…”

Ca2+ entry via TRPC1 is essential for cellular differentiation and modulates secretion via the SNARE complex

“…Although several nuclear receptors and transcription factors that regulate adipocyte differentiation and adipogenesis have been identified (Farmer, 2006), factors upstream to the activation of these transcription factors are still unknown. The activation of peroxisome proliferator-activated receptor γ (PPARγ) occurs in the intermediate or late stage of adipogenesis, and PPARγ activation has been determined to be a master regulator of adipogenesis (Haider et al, 2017). PPARγ has been linked to the transcription of genes expressed in mature adipocytes such as fatty acid binding protein (FABP4), required for transport of free fatty acids, and perilipin (PLIN1), which covers the surface of mature lipid droplets in adipocytes and regulates lipolysis.…”