AMP-activated protein kinase signaling in metabolic regulation

Abstract

AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. When activated by a deficit in nutrient status, AMPK stimulates glucose uptake and lipid oxidation to produce energy, while turning off energy-consuming processes including glucose and lipid production to restore energy balance. AMPK controls whole-body glucose homeostasis by regulating metabolism in multiple peripheral tissues, such as skeletal muscle, liver, adipose tissues, and pancreatic beta cells--key tissues in the pathogenesis of type 2 diabetes. By responding to diverse hormonal signals including leptin and adiponectin, AMPK serves as an intertissue signal integrator among peripheral tissues, as well as the hypothalamus, in the control of whole-body energy balance.

Figure 1. Structure and regulation of AMPK.

AMPK is a heterotrimeric complex consisting of an α, a β, and a γ subunit and is activated by the upstream kinases CaMKK and LKB1 via phosphorylation of threonine residue 172. Activation of AMPK by CaMKK and LKB1 is dependent on the intracellular calcium and AMP/ATP ratio, respectively. Generally, AMPK restores energy balance by activating processes that produce energy (e.g., lipid oxidation and glucose uptake) while inhibiting those that consume energy (e.g., protein synthesis).

Figure 2. Role of AMPK in the regulation of whole-body glucose homeostasis.

Activation of AMPK turns on ATP-generating processes, while switching off ATP-consuming processes. In skeletal muscle, acute activation of AMPK increases glucose uptake and lipid oxidation, while chronic activation of AMPK is associated with mitochondrial biogenesis. Activation of AMPK inhibits glucose and lipid synthesis in the liver but increases lipid oxidation. Lipolysis and lipogenesis in adipose tissue are also reduced by AMPK activation. Collectively, activation of AMPK in skeletal muscle, liver, and adipose tissue results in a favorable metabolic milieu for the prevention or treatment of T2D, i.e., decreased circulating glucose, reduced plasma lipid, and ectopic fat accumulation, as well as enhanced insulin sensitivity. Activation of pancreatic AMPK is associated with decreased insulin secretion, likely a protective measure to prevent hypoglycemia during food deprivation, although this effect needs to be considered in pharmaceutical targeting of AMPK for the treatment of T2D.

Figure 3. Integration of intertissue signaling by AMPK.

Adipocyte-derived leptin reduces food intake though inhibition of hypothalamic AMPK. Leptin increases skeletal muscle fatty acid oxidation via direct activation of AMPK and the hypothalamus–sympathetic nervous system axis. The involvement of hypothalamic AMPK in leptin-induced skeletal muscle lipid oxidation and glucose uptake is unknown. Adiponectin is secreted by adipose tissue and increases skeletal muscle lipid oxidation and glucose uptake, as well as suppressing liver glucose production by activating AMPK.