Endocrine Abstracts

Introduction: We have previously demonstrated that APPL1 maintains glucose homeostasis by promoting both actions and secretion of insulin. Although APPL2 is a close homolog of APPL1, the physiological function of APPL2 is vaguely characterized. Thus, we generated a knockout (KO) mouse model in which APPL2 is deleted in pancreatic β-cells and hypothalamus (which is called APPL2 KO mice) to investigate its role in glucose and energy metabolism.

Methods: Male APPL2 KO mice and their wild-type (WT) littermates were fed with standard chow for 12 weeks and then were subjected to acute cold challenge or chronic cold acclimation. A control group under thermoneutral condition was set as well. Basic metabolic parameters related to glucose and energy metabolism were examined.

Results: APPL2 KO mice displayed impairment of insulin secretion compared to its WT controls. Apart from the β-cell phenotypes, APPL2 KO mice displayed increased adiposity accompanied by a dramatic reduction of energy expenditure, despite of similar food intake and locomotor activity. Acute cold challenge experiment revealed that APPL2 KO mice are cold sensitive, which is due to defective lipolytic and thermogenic programs in adipose tissues. Chronic cold acclimation demonstrated that the ‘browning’ process in subcutaneous white adipose tissue was almost absent in APPL2 KO mice. Such defects were associated with elevated activity of AMPK in hypothalamus.

Conclusion: APPL2 not only modulates β-cell function but also regulates energy metabolism by controlling the hypothalamus-adipose tissue axis.