TY - JOUR
T1 - MAPK-interacting kinase 2 (MNK2) regulates adipocyte metabolism independently of its catalytic activity
AU - Merrett, James E.
AU - Xie, Jianling
AU - Psaltis, Peter J.
AU - Proud, Christopher G.
N1 - Funding Information:
This work was supported by funding from the South Australian Health and Medical Research Institute. JEM acknowledges the support received through the provision of an Australian Government Research Training Program Scholarship. PJP is supported by a L2 Future Leader Fellowship from the National Heart Foundation of Australia [FLF102056] and L2 Career Development Fellowship from the National Health and Medical Research Council [CDF1161506].
Funding Information:
This work was supported by funding from the South Australian Health and Medical Research Institute. JEM acknowledges the support received through the provision of an Australian Government Research Training Program Scholarship. PJP is supported by a L2 Future Leader Fellowship from the National Heart Foundation of Australia [FLF102056] and L2 Career Development Fellowship from the National Health and Medical Research Council [CDF1161506]. 3T3-L1 embryonic fibroblasts were generously provided by Dr. Yeesim Khew-Goodall from the Centre for Cancer Biology (University of South Australia, Adelaide, Australia). We thank the South Australian Health and Medical Research for their support for this work.
PY - 2020/7
Y1 - 2020/7
N2 - The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are serine/threonine protein kinases that are activated by the ERK1/2 (extracellular-regulated kinase) and p38α/β MAPK pathways. The MNKs have previously been implicated in metabolic disease and shown to mediate diet-induced obesity. In particular, knockout of MNK2 in mice protects from the weight gain induced by a high-fat diet. These and other data suggest that MNK2 regulates expansion of adipose tissue, a stable, long-term energy reserve that plays an important role in regulating whole-body energy homeostasis. Using the well-established mouse 3T3-L1 in vitro model of adipogenesis, the role of the MNKs in adipocyte differentiation and lipid storage was investigated. Inhibition of MNK activity using specific inhibitors failed to impair adipogenesis or lipid accumulation, suggesting that MNK activity is not required for adipocyte differentiation and does not regulate lipid storage. However, small-interfering RNA (siRNA) knockdown of MNK2 did reduce lipid accumulation and regulated the levels of two major lipogenic transcriptional regulators, ChREBP (carbohydrate response-element binding protein) and LPIN1 (Lipin-1). These factors are responsible for controlling expression of genes for proteins involved in de novo lipogenesis and triglyceride synthesis. Knockdown of MNK2 also increased the expression of hormone-sensitive lipase which catalyses the breakdown of triglyceride. These findings identify MNK2 as a regulator of adipocyte metabolism, independently of its catalytic activity, and reveal some of the mechanisms by which MNK2 drives adipose tissue expansion. The development of an MNK2-targeted therapy may therefore be a useful intervention for reducing weight caused by excessive nutrient intake.
AB - The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are serine/threonine protein kinases that are activated by the ERK1/2 (extracellular-regulated kinase) and p38α/β MAPK pathways. The MNKs have previously been implicated in metabolic disease and shown to mediate diet-induced obesity. In particular, knockout of MNK2 in mice protects from the weight gain induced by a high-fat diet. These and other data suggest that MNK2 regulates expansion of adipose tissue, a stable, long-term energy reserve that plays an important role in regulating whole-body energy homeostasis. Using the well-established mouse 3T3-L1 in vitro model of adipogenesis, the role of the MNKs in adipocyte differentiation and lipid storage was investigated. Inhibition of MNK activity using specific inhibitors failed to impair adipogenesis or lipid accumulation, suggesting that MNK activity is not required for adipocyte differentiation and does not regulate lipid storage. However, small-interfering RNA (siRNA) knockdown of MNK2 did reduce lipid accumulation and regulated the levels of two major lipogenic transcriptional regulators, ChREBP (carbohydrate response-element binding protein) and LPIN1 (Lipin-1). These factors are responsible for controlling expression of genes for proteins involved in de novo lipogenesis and triglyceride synthesis. Knockdown of MNK2 also increased the expression of hormone-sensitive lipase which catalyses the breakdown of triglyceride. These findings identify MNK2 as a regulator of adipocyte metabolism, independently of its catalytic activity, and reveal some of the mechanisms by which MNK2 drives adipose tissue expansion. The development of an MNK2-targeted therapy may therefore be a useful intervention for reducing weight caused by excessive nutrient intake.
UR - http://www.scopus.com/inward/record.url?scp=85089125627&partnerID=8YFLogxK
U2 - 10.1042/BCJ20200433
DO - 10.1042/BCJ20200433
M3 - Article
C2 - 32648926
SN - 0264-6021
VL - 477
SP - 2735
EP - 2754
JO - The Biochemical journal
JF - The Biochemical journal
IS - 14
ER -