TY - JOUR
T1 - Body weight control via protein kinase CK2: diet-induced obesity counteracted by pharmacological targeting
AU - Buchwald, Laura Michaela
AU - Pedersen, Ditte Neess
AU - Hansen, Daniel
AU - Doktor, Thomas Koed
AU - Ramesh, Vignesh
AU - Steffensen, Lasse Bach
AU - Blagoev, Blagoy
AU - Litchfield, David W
AU - Andresen, Brage Storstein
AU - Ravnskjær, Kim
AU - Færgeman, Nils Joakim K.
AU - Guerra, Barbara
PY - 2025/1
Y1 - 2025/1
N2 - Background: Protein kinase CK2 is a highly conserved enzyme implicated in the pathogenesis of various human illnesses including obesity. Despite compelling evidence for the involvement of this kinase in the pathophysiology of obesity, the molecular mechanisms by which CK2 might regulate fat metabolism are still poorly understood. Methods and results: In this study, we aimed to elucidate the role of CK2 on lipid metabolism by employing both in vitro and in vivo approaches using mouse pre-adipocytes and a mouse model of diet-induced obesity. We show that pharmacological inhibition of CK2 by CX-4945 results in premature upregulation of p27
KIP1 preventing the progression of cells into mature adipocytes by arresting their development at the intermediate phase of adipogenic differentiation. Consistent with this, we show that in vivo, CK2 regulates the expression levels and ERK-mediated phosphorylation of C/EBPβ, which is one of the earliest transcription factors responsive to adipogenic stimuli. Furthermore, we demonstrate the functional implication of CK2 in the expression of late markers of adipogenesis and factors regulating lipogenesis in liver and white adipose tissue. Finally, we show that while mice subjected to high-fat diet increased their body weight, those additionally treated with CX-4945 gained considerably less weight. NMR-based body composition analysis revealed that this is linked to significant differences in body fat mass. Conclusions: Taken together, our study provides novel insights into the role of CK2 in fat metabolism in response to chronic lipid overload and confirms CK2 pharmacological targeting as a potentially powerful strategy for body weight control and/or the treatment of obesity and related metabolic disorders.
AB - Background: Protein kinase CK2 is a highly conserved enzyme implicated in the pathogenesis of various human illnesses including obesity. Despite compelling evidence for the involvement of this kinase in the pathophysiology of obesity, the molecular mechanisms by which CK2 might regulate fat metabolism are still poorly understood. Methods and results: In this study, we aimed to elucidate the role of CK2 on lipid metabolism by employing both in vitro and in vivo approaches using mouse pre-adipocytes and a mouse model of diet-induced obesity. We show that pharmacological inhibition of CK2 by CX-4945 results in premature upregulation of p27
KIP1 preventing the progression of cells into mature adipocytes by arresting their development at the intermediate phase of adipogenic differentiation. Consistent with this, we show that in vivo, CK2 regulates the expression levels and ERK-mediated phosphorylation of C/EBPβ, which is one of the earliest transcription factors responsive to adipogenic stimuli. Furthermore, we demonstrate the functional implication of CK2 in the expression of late markers of adipogenesis and factors regulating lipogenesis in liver and white adipose tissue. Finally, we show that while mice subjected to high-fat diet increased their body weight, those additionally treated with CX-4945 gained considerably less weight. NMR-based body composition analysis revealed that this is linked to significant differences in body fat mass. Conclusions: Taken together, our study provides novel insights into the role of CK2 in fat metabolism in response to chronic lipid overload and confirms CK2 pharmacological targeting as a potentially powerful strategy for body weight control and/or the treatment of obesity and related metabolic disorders.
KW - Adipogenesis
KW - C/EBPβ
KW - CK2
KW - FASN
KW - Lipogenesis
KW - PPAR-γ
KW - p27
U2 - 10.1016/j.metabol.2024.156060
DO - 10.1016/j.metabol.2024.156060
M3 - Journal article
C2 - 39521118
SN - 0026-0495
VL - 162
JO - Metabolism
JF - Metabolism
M1 - 156060
ER -