PgmNr M5029: Sik1 is a key regulator of adipose mass, glucose and lipid metabolism in mice.

Authors:
D. West 1 ; S. Roy 1 ; AJ Nava 1 ; M. Adkisson 1 ; K. Lloyd 2


Institutes
1) Childrens Hospital of Oakland Research Institute, Oakland, CA; 2) University of California, Davis, CA.


Abstract:

SIK1 is a serine/threonine kinase belonging to a three-member AMP-activated protein kinase family.  Both SIK2 & SIK3 reportedly have roles in lipid and glucose metabolism in adipose tissue and liver respectively, while a functional role for SIK1 in adipose tissue or liver function has not been described.    In a preliminary study, we found decreased adipose depot mass in both female and male Sik1tm1(KOMP)Vlcg-/- mice at ~50-days-of-age mutants with normal body weight.  In a follow-up study conducted as part of the KOMP2 adult phenotyping pipeline (http://www.mousephenotype.org/impress), we found significant differences in body composition, glucose & lipid metabolism (all p < 0.0001; Mixed Model; n=8 F Sik1-/- , n=246 F Sik1+/+, n=8 M Sik1-/-, n=239 M Sik1+/+).  Compared to control mice, Sik1tm1.1(KOMP)Vlcg-/- mice exhibited dramatically reduced body fat and body fat/body mass ratios (fat mass/total mass:  F-/- = 0.13 ± 0.01; F+/+ = 0.186 ± 0.002; M-/- = 0.114 ± 0.01; F+/+ = 0.220 ± 0.003; Mean ± SEM), and a significantly increased lean mass/body mass ratio.  In addition, there were significant decreases in circulating total cholesterol, HDL-cholesterol, and insulin relative to controls, and a markedly improved area under the glucose tolerance test compared to controls.  At 50 days of age, Sik-/- male mice had significant alterations of gene expression in liver, muscle, and adipose tissue consistent with a derangement of lipid and glucose metabolism.  These data support a role for SIK1 in the regulation of adipose mass, glucose and lipid metabolism.  Supported by NIH grants U42OD011175, U54HG006364, DK085124.