Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel.

Miguel A Lanaspa,Swati Jain,Sandra L Martin,Peter Stenvinkel,Jessica Trostel,L Elaine Epperson,Takahiko Nakagawa,Colin T Mant,Christopher J Rivard,Christina Cicerchi,Takuji Ishimoto,Michiko Shimada,Laura Gabriela Sanchez-Lozada,Nanxing Li,Alkesh Jani,Gabriela E Garcia,Richard J Johnson,Carlos A Roncal-Jimenez,Miguel López

doi:10.1371/journal.pone.0123509

Abstract

Hibernating animals develop fatty liver when active in summertime and undergo a switch to a fat oxidation state in the winter. We hypothesized that this switch might be determined by AMP and the dominance of opposing effects: metabolism through AMP deaminase (AMPD2) (summer) and activation of AMP-activated protein kinase (AMPK) (winter). Liver samples were obtained from 13-lined ground squirrels at different times during the year, including summer and multiples stages of winter hibernation, and fat synthesis and β-fatty acid oxidation were evaluated. Changes in fat metabolism were correlated with changes in AMPD2 activity and intrahepatic uric acid (downstream product of AMPD2), as well as changes in AMPK and intrahepatic β-hydroxybutyrate (a marker of fat oxidation). Hepatic fat accumulation occurred during the summer with relatively increased enzymes associated with fat synthesis (FAS, ACL and ACC) and decreased enoyl CoA hydratase (ECH1) and carnitine palmitoyltransferase 1A (CPT1A), rate limiting enzymes of fat oxidation. In summer, AMPD2 activity and intrahepatic uric acid levels were high and hepatic AMPK activity was low. In contrast, the active phosphorylated form of AMPK and β-hydroxybutyrate both increased during winter hibernation. Therefore, changes in AMPD2 and AMPK activity were paralleled with changes in fat synthesis and fat oxidation rates during the summer-winter cycle. These data illuminate the opposing forces of metabolism of AMP by AMPD2 and its availability to activate AMPK as a switch that governs fat metabolism in the liver of hibernating ground squirrel.

Highlights

Body weight is tightly regulated in most species
During hibernation we could not observe significant differences between different stages we found a tendency to be lower in interbout arousal period (IBA) and Entering torpor compared with the rest of groups
While much of the excessive fat is stored in the abdominal adipose depots, the liver is another prime site for fat storage for many animals [33]

Summary

Introduction

Body weight is tightly regulated in most species. Keesey et al have shown that rats return to their baseline weight after either force feeding or force fasting [1]. Migrating songbirds that fast during the summer regain their weight during the recovery phase [2]. In both situations the animals return to their baseline weight for their age and the time of the year. The Emperor penguin (Aptenodytes forsteri) doubles its body weight in fat to survive for up to 4 months on the Antarctic ice during brooding [3]. Hibernating mammals provide excellent examples of animals that gain large amounts of fat and lose it while fasting throughout winter [4]

Methods

Results

Conclusion