The role of S6K1 in development and maintenance of nutrient homeostasis

Insulin signaling at the target tissue results in a large array of biological
functions. These events are essential for normal growth and development and for
normal nutrient homeostasis. Studying the signaling pathways involved in insulin
and nutrient action could lead to better understanding of pathophysiology of
insulin resistance associated with obesity and type 2 diabetes and identifying key
molecules and processes could lead to the development of therapeutic strategies
for the treatment of these common disorders.
Previously mice deficient for S6 Kinase 1 (S6K1), an effector of the
mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin
signals, were shown to be hypoinsulinaemic, glucose intolerant and have
reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose
levels during fasting, suggesting hypersensitivity to insulin, raising the question of
their metabolic fate as a function of age and diet. The present study shows that
S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation
and sensitive to insulin owing to the apparent loss of a negative feedback loop
from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and
S636/S639 phosphorylation; sites involved in insulin resistance, Thus under
conditions of nutrient satiation S6K1 negatively regulates insulin signaling.
The actual cause of diminished β-cell size in adult S6K1-deficient mice
has not been fully understood. The present study shows that loss of S6K1 leads
to reduced β-cell size during development, intrauterine growth retardation, and
impaired placental development. S6K1 deficient embryos supplied with a wild
type normal placenta by tetraploid aggregation, developed normally and only β-
cell size was still smaller than wild type, suggesting the defect in β-cell growth is
independent of placental dysfunction. Furthermore, β-cell specific transgenic
expression of S6K1 restores β-cell growth and development in S6K1 deficient
embryos.
The present study indicates the impact of S6KI signaling in age- and dietinduced
obesity and insulin resistance, and also gives insight into the interaction between insulin induced IRS-PI3K pathway and nutrient induced mTOR-S6K
pathway in pancreatic β-cell growth and nutrient homeostasis.