Identification of T cell derived KLK1b22 as a novel regulator of systemic metabolism

In an effort to understand the role of mTORC1 in regulating T cell differentiation, we generated mice in which Rheb is selectively deleted in T cells (T-Rheb -/- mice). During the course of these studies we noted that the T-Rheb -/- mice were heavier with a higher percentage of body fat when compared to Wt mice. Surprisingly, such mice had decreased fasting blood glucose, improved glucose tolerance and sensitivity to insulin. Indeed, even when placed on a high fat diet, the T-Rheb -/- mice demonstrated increased VO2, VCO2 and energy expenditure as well as increased glucose tolerance. Additionally, the T-Rheb -/- inguinal adipose tissue pad showed beige adipose tissue development with the expression of UCP1, Cidea, and CPT1b. Analysis of the perigonadal white adipose tissue pad revealed that T-Rheb -/- mice have increased T regulatory cells. In an effort to determine the mechanism by which the Rheb -/- T cells promote this effect, microarray analysis was performed. These studies revealed a marked increase in kallikrein 1-related peptidase b22 (KLK1b22), which is normally only expressed in the mouse salivary gland. Overexpression of KLK1b22 in cells in vitro markedly enhances insulin receptor signaling. Furthermore, transduction of Wt mice with an adenovirus expressing KLK1b22 or treatment with recombinant KLK1b22 enhances glucose tolerance. Interestingly, an Immunological Genome Project mouse screen identified that 129S1/SVLMJ and C3HEJ mice express KLK1b22 in naïve CD4+ T cells. Further investigation revealed that 129 and C3H mice have improved glucose tolerance when compared to Wt C57B6 mice. Since KLK1b22 is a mouse specific protein, an in vitro screen was performed utilizing adenoviruses expressing each of the 15 human kallikreins. This screen resulted in identifying human tissue kallikreins 6 and 10 as potential mediators of glucose tolerance. Overall our studies reveal a novel role for T cells, via the expression of KLK1b22, in regulating glucose metabolism and beige adipose tissue generation