Endocrine Abstracts

Obesity is usually considered to be a forerunner to insulin resistance (IR). Using in vitro studies, we have identified a role for the giant protein AHNAK in regulating Glut4 expression and function. Ex vivo analysis of white adipose tissue from ob/ob mice and aged/obese rats exhibited elevated AHNAK protein levels (2.3- and 3- fold) with concomitant reduction in Glut4 levels (5- and 2-fold).

The aim of this study was to investigate the role of AHNAK in overall metabolic homeostasis using AHNAK knockout (KO) mice. When challenged with high fat-diet (HFD) for 12 weeks, AHNAK KO mice were protected from DIO as reflected by a 50% reduced adipose tissue mass, 25% reduced body weight and 37% increased lean body mass, compared to wild type (WT) mice on HFD. KO mice exhibited IR as evident from their glucose (AUC 28412 vs 34307) and insulin (AUC 12645 vs 15056) tolerance tests. Fasting blood glucose levels were 17% elevated while plasma insulin levels were 37% reduced in KO-HFD compared to WT-HFD. Contrary to the in vitro results, Glut4 levels in adipose tissue obtained from either KO-chow or KO-HFD were 35 and 20% reduced compared to WT-chow. Real-time PCR analysis showed no change in levels of adipogenic genes PPARgamma and CD36, while muscle and liver SCD-1 levels were 4-fold upregulated in KO. The expression of G-6-Pase, key gluconeogenetic enzyme, was higher in KO compared to WT mice.

Taken together, our data show dissociation between DIO and IR in AHNAK KO mice. AHNAK has an important role in weight control, but AHNAK deficiency impairs insulin sensitivity in vivo. Therefore, careful regulation of AHNAK is essential for the management of metabolic homeostasis.