S6 Kinase 2 Deficiency Improves Glucose Disposal in Mice Fed a High Fat Diet

Kristin M Taylor

doi:10.4172/2155-6156.1000441

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) regulates insulin-mediated glucose metabolism, cell proliferation, the oxidative branch of the pentose phosphate pathway, de novo lipogenesis, and autophagy. Ribosomal S6 kinase 1 (S6K1) and 2 (S6K2) are downstream effectors of mTORC1. To characterize the role of S6K2 in insulin-mediated metabolism, the response of S6K2 deficient mice (S6K2-/-) to a glucose challenge was compared to that of wild-type (C57BL/6) and diabetes resistant strains (BALB/c and A/J) after 35 weeks on a high fat diet (HFD). Although S6K2-/- mice fed a HFD gained as much weight as the wild-type C57BL/6 control mice, unlike the wild-type mice they remained glucose tolerant, insulin sensitive, and had lower basal blood glucose levels. Moreover, unlike S6K1 deficient mice, S6K2-/- mice have increased basal plasma insulin levels and increased β-cell mass compared to C57BL/6, BALB/c, and A/J mice. Administration of insulin to S6K2-/- and C57BL/6 mice fed a Standard Diet (SD) resulted in phosphorylation of Ser307 on skeletal muscle Insulin Receptor Substrate 1 (IRS-1); however, when both strains were fed a HFD, phosphorylation of IRS-1 Ser307 was maintained in S6K2-/- mice but inhibited in C57BL/6 mice. Taken together, these results suggest that S6K2 inhibition may represent a strategy for treating type 2 diabetes.

Highlights

The mammalian Target of Rapamycin senses cellular energy and can either promote cell growth and proliferation or induce catabolism and autophagy. mTOR is a conserved serine/threonine kinase that exists in several distinct multi-protein complexes such as mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 [13]. mTORC1 regulates autophagy and metabolic pathways, including glycolysis, de novo lipid biosynthesis, and the oxidative arm of the pentose phosphate pathway [4]
We demonstrated that S6 kinase 2 (S6K2)-/- mice on Standard Diet (SD) have higher basal plasma insulin levels than C57BL/6, BALB/c and A/J mice
As S6K2 is downstream of the mTORC1 signaling pathway, we asked whether a reduction in its levels would affect the basal levels of IRβ and Insulin Receptor Substrate 1 (IRS-1)

Summary

Introduction

The mammalian Target of Rapamycin (mTOR) senses cellular energy and can either promote cell growth and proliferation or induce catabolism and autophagy. mTOR is a conserved serine/threonine kinase that exists in several distinct multi-protein complexes such as mTORC1 (containing raptor) and mTORC2 (containing rictor) [13]. mTORC1 regulates autophagy and metabolic pathways, including glycolysis, de novo lipid biosynthesis, and the oxidative arm of the pentose phosphate pathway [4]. The mammalian Target of Rapamycin (mTOR) senses cellular energy and can either promote cell growth and proliferation or induce catabolism and autophagy. An additional mTORC1-regulated pathway was revealed when we treated Pompe mice with rapamycin and observed the abatement of lysosomal glycogen accumulation in skeletal muscle [5]. A better understanding of how mTORC1 interfaces with these diverse metabolic pathways in different tissues may lead to new therapies to treat Pompe disease as well as other metabolic disorders such as type 2 diabetes. S6K1 deficient mice on a High Fat Diet (HFD) exhibit improved insulin sensitivity and are protected against obesity when compared to HFD-fed wild-type controls [6]. Inhibiting S6K1 is currently being considered as a potential strategy to treat type 2 diabetes [7]. S6K1 deficient mice on a Standard Diet (SD) are glucose intolerant, hypoinsulinemic, and have reduced β-cell mass [8]

Objectives

Results

Conclusion