Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis

Abstract

Obesity results from an excessive expansion of white adipose tissue (WAT) from hypertrophy of preexisting adipocytes and enhancement of precursor differentiation into mature adipocytes. We report that Nck2-deficient mice display progressive increased adiposity associated with adipocyte hypertrophy. A negative relationship between the expression of Nck2 and WAT expansion was recapitulated in humans such that reduced Nck2 protein and mRNA levels in human visceral WAT significantly correlate with the degree of obesity. Accordingly, Nck2 deficiency promotes an adipogenic program that not only enhances adipocyte differentiation and lipid droplet formation but also results in dysfunctional elevated lipogenesis and lipolysis activities in mouse WAT as well as in stromal vascular fraction and 3T3-L1 preadipocytes. We provide strong evidence to support that through a mechanism involving primed PERK activation and signaling, Nck2 deficiency in adipocyte precursors is associated with enhanced adipogenesis in vitro and adiposity in vivo. Finally, in agreement with elevated circulating lipids, Nck2-deficient mice develop glucose intolerance, insulin resistance, and hepatic steatosis. Taken together, these findings reveal that Nck2 is a novel regulator of adiposity and suggest that Nck2 is important in limiting WAT expansion and dysfunction in mice and humans.

Adipocyte biology: It is time to upgrade to a new model

“…Nck2 expression was also found to be reduced in the omental fat of obese human subjects, and taken together, these data suggest a role for Nck2 in limiting hypertrophic adipose tissue expansion and maintaining normal adipocyte function (Dusseault et al, 2016).…”

Nck2, an unexpected regulator of adipogenesis

“…25 In addition, we uncovered that among severely-obese humans, Nck2 expression is downregulated in visceral white adipose tissue, 25 while it is upregulated during differentiation of human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes (Fig. 1).…”

“…2D). Interestingly, higher expression of PPARg may represent an adaptive response to lower PPARg activity that may be in fact ascribed to lower level of Fabp4 mRNA, 25 which could potentially results in low level of Fabp4 (aP2), a condition that has been previously reported to mediate a negative feedback loop on PPARg expression. 45 However, Nck2 overexpression hampered PPARg nuclear translocation, as revealed by immunofluorescence (Fig.…”

“…25 As described above, induction of PPARg is the primary driver of adipocyte differentiation and Fabp4 expression, resulting from the early induction of the transcription factors C/EBPb and C/EBPd during adipogenesis. In Nck2 overexpressing 3T3-L1 preadipocytes subjected to the classical hormonal differentiation protocol, the levels of C/EBPb and C/EBPa mRNAs are equivalent to the levels found in similarly treated, empty-vector-transfected 3T3-L1 cells (Fig.…”

“…41 During adipocyte differentiation and in adipose tissue, we found that the deficiency of Nck2 results in increased PERK activity and signaling, correlating with higher expression of lipogenic genes. 25 PERK activation leads to phosphorylation of the eukaryotic initiation factor 2 a-subunit (peIF2a), which reduces overall rate of translation initiation, but simultaneously upregulates expression of transcription factors such as activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). 42,43 Through the peIF2a-ATF4 canonical pathway, PERK critically contributes to fat storage and lipogenesis by inducing lipogenic genes expression during adipocyte differentiation in multiple cell types via ATF4-induced expression of the ER membrane-bound transcription factor sterol element binding 1c (SREBP1c).…”