Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance.

Overnutrition-induced endothelial inflammation plays a crucial role in high fat diet (HFD)-induced insulin resistance in animals. Endothelial glycolysis plays a critical role in endothelial inflammation and proliferation, but its role in diet-induced endothelial inflammation and subsequent insulin resistance has not been elucidated. PFKFB3 is a critical glycolytic regulator, and its increased expression has been observed in adipose vascular endothelium of C57BL/6J mice fed with HFD in vivo, and in palmitate (PA)-treated primary human adipose microvascular endothelial cells (HAMECs) in vitro. We generated mice with Pfkfb3 deficiency selective for endothelial cells to examine the effect of endothelial Pfkfb3 in endothelial inflammation in metabolic organs and in the development of HFD-induced insulin resistance. EC Pfkfb3-deficient mice exhibited mitigated HFD-induced insulin resistance, including decreased body weight and fat mass, improved glucose clearance and insulin sensitivity, and alleviated adiposity and hepatic steatosis. Mechanistically, cultured PFKFB3 knockdown HAMECs showed decreased NF-κB activation induced by PA, and consequent suppressed adhesion molecule expression and monocyte adhesion. Taken together, these results demonstrate that increased endothelial PFKFB3 expression promotes diet-induced inflammatory responses and subsequent insulin resistance, suggesting that endothelial metabolic alteration plays an important role in the development of insulin resistance.

[1]  J. Sowers,et al.  Obesity, Adipose Tissue and Vascular Dysfunction. , 2021, Circulation research.

[2]  M. Mittelbrunn,et al.  Glycolysis – a key player in the inflammatory response , 2020, The FEBS journal.

[3]  M. Koschinsky,et al.  Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation , 2020, Circulation research.

[4]  E. Pålsson-McDermott,et al.  Targeting immunometabolism as an anti-inflammatory strategy , 2020, Cell Research.

[5]  Yunchao Su,et al.  Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia. , 2019, Pharmacological research.

[6]  D. Stepp,et al.  Endothelial adenosine kinase deficiency ameliorates diet-induced insulin resistance. , 2019, The Journal of endocrinology.

[7]  M. Zhang,et al.  PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension , 2019, Proceedings of the National Academy of Sciences.

[8]  Chunxiang Zhang,et al.  PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis , 2018, Nature Communications.

[9]  M. Graupera,et al.  Endothelial Cells: New Players in Obesity and Related Metabolic Disorders , 2018, Trends in Endocrinology & Metabolism.

[10]  Ranran Li,et al.  The Glycolytic Enzyme PFKFB3 Controls TNF-α-Induced Endothelial Proinflammatory Responses , 2018, Inflammation.

[11]  Ranran Li,et al.  The Glycolytic Enzyme PFKFB3 Controls TNF-α-Induced Endothelial Proinflammatory Responses , 2018, Inflammation.

[12]  C. Patterson,et al.  Emerging Roles of Vascular Endothelium in Metabolic Homeostasis. , 2018, Circulation research.

[13]  F. Villarroya,et al.  Inflammation of brown/beige adipose tissues in obesity and metabolic disease , 2018, Journal of internal medicine.

[14]  H. Jo,et al.  Mechanical Activation of Hypoxia-Inducible Factor 1 alpha Drives Endothelial Dysfunction at Atheroprone Sites , 2022 .

[15]  Z. Dong,et al.  Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation , 2017, Nature Communications.

[16]  Lois E. H. Smith,et al.  Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis , 2017, Nature Communications.

[17]  J. Shao,et al.  Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. , 2017, Biochemical and biophysical research communications.

[18]  C. Weber,et al.  Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis , 2017, EMBO molecular medicine.

[19]  D. Duncker,et al.  The microcirculation: a key player in obesity-associated cardiovascular disease , 2017, Cardiovascular research.

[20]  N. Prabhakar,et al.  HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium , 2017, eLife.

[21]  P. Carmeliet,et al.  Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. , 2016, Cancer cell.

[22]  B. Heit,et al.  Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis. , 2015, American journal of physiology. Endocrinology and metabolism.

[23]  A. Descoteaux,et al.  Macrophage Cytokines: Involvement in Immunity and Infectious Diseases , 2014, Front. Immunol..

[24]  Yunchao Su,et al.  Endothelial PFKFB3 Plays a Critical Role in Angiogenesis , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[25]  P. Carmeliet,et al.  Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. , 2014, Cell metabolism.

[26]  Shiping Ma,et al.  Homoplantaginin modulates insulin sensitivity in endothelial cells by inhibiting inflammation. , 2012, Biological & pharmaceutical bulletin.

[27]  S. Nagamachi,et al.  Inhibition of Development of Abdominal Aortic Aneurysm by Glycolysis Restriction , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[28]  L. Thibault,et al.  High-fat diet-induced obesity in animal models , 2010, Nutrition Research Reviews.

[29]  G. Zaloga,et al.  Long-chain saturated fatty acids induce pro-inflammatory responses and impact endothelial cell growth. , 2010, Clinical nutrition.

[30]  A. Klip,et al.  Direct and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells , 2009, Archives of physiology and biochemistry.

[31]  Shuichi Kaneko,et al.  Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria , 2009, Journal of Biological Chemistry.

[32]  S. Menini,et al.  Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice. , 2009, Gastroenterology.

[33]  A. Hasty,et al.  Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. , 2008, Future lipidology.

[34]  M. Scadeng,et al.  Bone marrow–specific Cap gene deletion protects against high-fat diet–induced insulin resistance , 2007, Nature Medicine.

[35]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB , 2005, Nature Medicine.

[36]  D. Vertommen,et al.  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. , 2004, The Biochemical journal.

[37]  K. Ajuwon,et al.  Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. , 2005, The Journal of nutrition.

[38]  Chaodong Wu,et al.  Regulation of the regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. , 2004, Advances in enzyme regulation.