Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia

Abstract

Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo. After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice.

Insulin action and resistance in obesity and type 2 diabetes

“…Moreover, attenuation of the hyperinsulinemia in genetically obese mice by treatment with streptozotocin or diazoxide reduces adipose tissue inflammation and increases insulin responsiveness 54 . Similar improvement in glucose tolerance is seen by reducing hyperinsulinemia in a mouse knockout model that impairs beta cell insulin secretion 55 .…”

Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium

“…Wong et al had shown that fatty acid β‐oxidation was higher in LECs than in arterial, venous, and microvascular BECs, whereas glycolytic flux was lower, suggesting the important role of mitochondrial oxidation in LEC metabolism. Studies have also shown that Map4k4 impairs energy metabolism in ECs and promotes insulin resistance during high‐fat diet‐induced obesity and its systemic loss improves insulin sensitivity . Primary ECs that were a mixture of lymphatic and blood ECs showed enhanced glycolytic and mitochondrial respiration in the absence of MAP4K4.…”

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

“…[101]. The role of protein kinase Map4k4 has been further discussed in obesity-induced hyperinsulinemia and insulin resistance by promoting insulin secretion from β cells [103]. Involvement of the MAPK signaling pathways has been recently reported in mediating the beneficial effects of tartary buckwheat flavonoids on redox balance and insulin resistance in insulin-resistant HepG2 cells [104].…”