AMP-activated protein kinase (AMPK) senses and maintains energy balance in peripheral tissues. When energy is deficient, AMPK activation leads to altered cellular metabolism and gene expression to inhibit anabolic processes, stimulate catabolism, and restore ATP. The CNS integrates diverse central and peripheral signals to maintain homeostasis. CNS AMPK is shown to have important, but complex roles in energy balance. CNS neurons sense their own energy needs, while some also integrate neuro-humoral signals to assess organismal energy balance. In the brain, AMPK is involved in both arenas, coordinating context-specific metabolic responses in many tissues. AMPK plays roles in both physiological (feeding) and pathophysiological (ischemic) states. During the latter, AMPK is highly activated to restore neuronal energy balance, but its over-activation may be deleterious. In this study, we review AMPK regulation and responses to cellular and organismal energy challenges in the CNS. AMP-activated protein kinaseAMP-activated protein kinase is a serine/threonine kinase with a catalytic a subunit and regulatory b and c subunits. AMPK not only senses energy status, but also functions at the tissue and organism levels to promote context-specific responses to physiological signals of metabolic status. AMPK modulates many aspects of cellular metabolism (Fig. 1a). AMPK was first known to be activated by ATP depletion (increased AMP/ATP ratio) and related stimuli (exercise, starvation, hypoxia, cellular pH and redox status, increased creatine/phosphocreatine ratio). However, AMPK is also activated by certain drugs, hormones, and cellular stressors that do not alter AMP/ATP ratio.

A potential role for fatty acid metabolism in the regulation of energy balance in the brain or in the periphery has been considered only recently. Fatty acid synthase (FAS) catalyzes the synthesis of long-chain fatty acids, whereas the breakdown of fatty acids by beta-oxidation is regulated by carnitine palmitoyltransferase-1, the rate-limiting enzyme for the entry of fatty acids into the mitochondria for oxidation. While the question of the physiological role of fatty acid metabolism remains to be resolved, studies indicate that inhibition of FAS or stimulation of carnitine palmitoyltransferase-1 using cerulenin or synthetic FAS inhibitors reduces food intake and incurs profound and reversible weight loss. Several hypotheses regarding the mechanisms by which these small molecules mediate their effects have been entertained. Centrally, these compounds alter the expression of hypothalamic neuropeptides, generally reducing the expression of orexigenic peptides. Whether through central, peripheral, or combined central and peripheral mechanisms, these compounds also increase energy consumption to augment weight loss. In vitro and in vivo studies indicate that at least part of C75's effects is mediated by modulation of adenosine monophosphate-activated protein kinase, a member of an energy-sensing kinase family. These compounds, with chronic treatment, also alter gene expression peripherally to favor a state of enhanced energy consumption. Together, these effects raise the possibility that pharmacological alterations in fatty acid synthesis/degradation may serve as a target for obesity therapeutics.

Understanding the mechanisms that govern neuronal responses to oxidative and metabolic stress is essential for therapeutic intervention. In vitro modeling is an important approach for these studies, as the metabolic environment influences neuronal responses. Surprisingly, most neuronal culture methods employ conditions that are non-physiological, especially with regards to glucose concentrations, which often exceed 20 mM. This concentration is a significant departure from physiological glucose levels, and even several-fold greater than that seen during severe hyperglycemia. The goal of this study was to establish a physiological neuronal culture system that will facilitate the study of neuronal energy metabolism and responses to metabolic stress. We demonstrate that the metabolic environment during preparation, plating, and maintenance of cultures affects neuronal viability and the response of neuronal pathways to changes in energy balance.