AMPK and autophagy in glucose/glycogen metabolism

Abstract

Glucose/glycogen metabolism is a primary metabolic pathway acting on a variety of cellular needs, such as proliferation, growth, and survival against stresses. The multiple regulatory mechanisms underlying a specific metabolic fate have been documented and explained the molecular basis of various pathophysiological conditions, including metabolic disorders and cancers. AMP-activated protein kinase (AMPK) has been appreciated for many years as a central metabolic regulator to inhibit energy-consuming pathways as well as to activate the compensating energy-producing programs. In fact, glucose starvation is a potent physiological AMPK activating condition, in which AMPK triggers various subsequent metabolic events depending on cells or tissues. Of note, the recent studies show bidirectional interplay between AMPK and glycogen. A growing number of studies have proposed additional level of metabolic regulation by a lysosome-dependent catabolic program, autophagy. Autophagy is a critical degradative pathway not only for maintenance of cellular homeostasis to remove potentially dangerous constituents, such as protein aggregates and dysfunctional subcellular organelles, but also for adaptive responses to metabolic stress, such as nutrient starvation. Importantly, many lines of evidence indicate that autophagy is closely connected with nutrient signaling modules, including AMPK, to fine-tune the metabolic pathways in response to many different cellular cues. In this review, we introduce the studies demonstrating the role of AMPK and autophagy in glucose/glycogen metabolism. Also, we describe the recent advances on their contributions to the metabolic disorders.

Introduction

As a primary energy source, glucose places on central blocks of metabolism in the whole body. Glucose falls into a Krebs cycle not only to produce energy by oxidative phosphorylation but also to provide biosynthetic intermediates for fatty acid, amino acid, and nucleotides, depending on cellular needs. Also, it is stored as glycogen, essentially in liver and muscles. Importantly, the metabolic regulation of glucose/glycogen is quite different between tissues, for example, liver (to maintain blood glucose level) and muscle (to provide cellular energy). Therefore, glucose metabolism is tightly regulated, and it includes the multiple layers of molecular networks for many different metabolic results between tissues. Many lines of evidence have identified a variety of signaling molecules to regulate glucose/glycogen metabolism in response to distinct metabolic stress. Among them, AMP-activated protein kinase (AMPK) has been extensively demonstrated as an important metabolic regulator functioning on various metabolic stresses, in which AMPK inhibits anabolic pathway and simultaneously activates catabolic pathway for energy homeostasis. Interestingly, accumulating reports have shown that lysosomal-dependent catabolic program, autophagy, plays important roles in macromolecular nutrient degradation, such as glycogen and lipid droplets. In addition to canonical degradation of glycogen by glycogen phosphorylase, autophagy-dependent glycogen degradation is reported as an important glucose-supplying alternative like gluconeogenesis. The accumulating lines of evidence showing the interplay between autophagy and carbohydrate metabolism reveal the existence of a dynamic feedback between autophagy and cellular energy balance. The recent advances on the molecular machinery on autophagy have allowed studying the molecular basis underlying the functional interaction between autophagy and cellular metabolism. Furthermore, much effort has revealed that a number of nutrient signaling molecules, including AMPK, are involved in the regulation of autophagy. Here, we discuss the regulation between AMPK, autophagy, and glucose/glycogen metabolism, as well as the alterations of such control in the metabolic disorders.