AMPK and the neuroendocrine regulation of appetite and energy expenditure

Abstract

This review highlights recent advances in the hormonal control of hypothalamic AMPK activity and the impact on appetite and energy metabolism. AMPK is an intracellular energy sensor that switches off ATP-consuming pathways and switches on ATP-producing pathways such as glucose uptake and fatty acid oxidation. In this regard, it is well positioned to respond to dynamic changes in metabolic state and nutritional over- or under-supply. Within the hypothalamus, AMPK responds to peripheral hormones that convey metabolic information based on increased plasma concentrations. For example, negative energy balance increases plasma ghrelin concentrations, increases hypothalamic AMPK and drives food intake. Conversely, plasma leptin concentrations are secreted in proportion to adipose levels and leptin suppresses hypothalamic AMPK activity and restricts food intake. This review explains that hypothalamic AMPK mediates neuroendocrine feedback control of energy metabolism. A current working model suggests that endocrine feedback influences hypothalamic AMPK via a number of mechanisms designed to shift an organism from negative to neutral energy balance. These mechanisms include (1) ghrelin stimulation of AMPK in NPY/AgRP in the arcuate nucleus (2) ghrelin stimulation of AMPK in the ventromedial hypothalamic nucleus, (3) a novel ghrelin-stimulated AMPK-dependent presynaptic mechanism that sustains AgRP neuron firing via a local synaptic memory system, (4) adiponectin stimulation of hypothalamic AMPK and (5) hypothalamic AMPK control of energy expenditure by thyroid hormone or leptin. The number of diverse mechanisms ensures hypothalamic AMPK drives the shift from negative to neutral energy balance and underscores the fundamental importance of hypothalamic AMPK to maintain neutral energy balance.

Introduction

Central neural circuits and peripheral target tissues regulate appetite and body weight in a coordinated and cohesive fashion involving negative feedback. A key component of this negative feedback action is the synthesis and release of peripheral metabolic hormones, such as leptin and ghrelin from adipose tissue and the stomach respectively. These hormones target core hypothalamic nuclei regulating appetite and energy metabolism, including the ventromedial hypothalamic nucleus (VMH), the lateral hypothalamus (LH), dorsomedial hypothalamic nucleus (DMH), the paraventricular nucleus (PVN) and the arcuate nucleus (ARC). An important role for the hypothalamus in energy metabolism was first discovered over 100 years ago, when it was noted that hypothalamic injury, but not pituitary injury resulted in marked obesity. Hetherington and Ranson demonstrated conclusively that this marked obesity was due to electrolytic lesions of the hypothalamus and identified the VMH as a key “satiety center” (Hetherington and Ranson, 1940). The presence of a hypothesized hypothalamic “feeding center” wasn’t discovered until 1951 when Anand and Brobeck showed that bilateral destruction of the LH completely suppressed spontaneous eating and labeled the LH as the “feeding center” (Anand and Brobeck, 1951). The ARC lies just below the VMH on either side of the third ventricle immediately adjacent to the fenestrated capillaries in the median eminence. This position permits ARC neurons to sense hormonal and nutrient fluctuations in the plasma.

There are two key appetite-regulating neuronal populations in ARC (Fig. 1). Neuropeptide Y (NPY) and agouti-related peptide AgRP are co-expressed in ARC neurons and are potent orexigenic peptides, whereas the proopiomelanocortin (POMC) precursor protein is cleaved into the potent anorexigenic α-melanocyte-stimulating hormone (α-MSH) peptide. The NPY/AgRP neurons will be referred to as AgRP neurons in this review as AgRP is only expressed in the ARC, whereas NPY is expressed in many other brains regions. AgRP and POMC neurons in the ARC are arguably considered “first-order” sensory neurons in the control of food intake and receive, coordinate and respond to changes in metabolic status. Both AgRP and POMC neurons project to the PVN, where the anorectic effects of α-MSH peptides are mediated by melanocortin 4 receptors (MC4R). NPY Y1 and Y5 receptors in the PVN mediate the orexigenic effects of NPY, whereas AgRP antagonizes the effect of α-MSH on the MC4R (Fig. 1). A unique feature of the melanocortin system is the ability of AgRP neurons to suppress POMC cell firing via inhibitory GABAergic inputs (Andrews et al., 2008, Cowley et al., 2003). There is no evidence that POMC neurons feed back to inhibit AgRP neuronal firing despite the expression of GABA in POMC neurons (Hentges et al., 2004, Hentges et al., 2009).

The regulation of these neurons by hormonal negative feedback is a fundamental component maintaining neutral energy balance. Ghrelin and leptin are two important hormones that convey metabolic information back to the brain. Plasma ghrelin concentrations increase under conditions of fasting or calorie restriction (Briggs and Andrews, 2011, Tschop et al., 2000) whereas plasma leptin concentrations increase with adiposity (Zhang et al., 1994). Therefore, ghrelin and leptin signal negative and positive energy balance, respectively, to the brain. The brain must receive, integrate and process this metabolic information and direct subtle changes in appetite and/or energy expenditure to maintain energy homeostasis.

Over the last 10–15 years, we have made significant advances in understanding the neuroendocrine circuits regulating appetite. It is clear from anatomical and physiological studies that ghrelin and leptin feedback to AgRP and POMC neurons to regulate appetite and body weight (Fig. 1). For example, ghrelin receptors are located on approximately 90% of AgRP neurons in the ARC (Willesen et al., 1999) and deletion of NPY and AgRP (Chen et al., 2004) or ablation of AgRP neurons prevents ghrelin-induced food intake (Luquet et al., 2007). Furthermore, ghrelin receptor (GHSR) knockout mice do not respond to peripheral or central injections of ghrelin (Zigman et al., 2005). On the other hand, POMC neurons express abundant leptin receptor and leptin injection activates POMC neurons, induces pSTAT3 signaling and reduces food intake (Gautron and Elmquist, 2011). Recent work indicates that subpopulations of leptin- and insulin-responsive POMC neurons exist, and leptin’s action on POMC neurons is an important regulator of glucose and energy metabolism (Gautron and Elmquist, 2011, Hill et al., 2010, Williams et al., 2010).

Adjacent to the ARC, the VMH has also emerged as an important leptin-sensitive hypothalamic nucleus with abundant leptin receptor expression particularly in the dorsomedial region (Zhang et al., 2011). Indeed, studies show that the VMH provides a strong excitatory input to POMC neurons and fasting diminishes the strength of the excitatory input from the VMH to POMC neurons (Fig. 1) Sternson et al., 2005. Deletion of leptin receptors from POMC neurons (Balthasar et al., 2004) or re-expression of leptin receptors on POMC neurons shows a minor effect on food intake (Huo et al., 2009), but a strong effect on whole body glucose metabolism (Huo et al., 2009). The effect of leptin to inhibit food intake may be driven largely through the VMH input onto POMC neurons. Indeed, deleting glutamate synaptic transmission from VMH neurons, increased long-term food intake and susceptibility to diet-induced obesity (Tong et al., 2007). This suggests that the major excitatory output from the VMH is to suppress food intake, presumably acting on the POMC neurons. While these studies highlight the central appetite circuits responding to hormonal inputs, little is known about the intracellular enzymes controlling energy metabolism and how they respond to hormonal or nutrient feedback signals. Over the last 5 years, AMP-activated kinase (AMPK) in the hypothalamus has emerged as a key kinase regulating neuroendocrine feedback control of appetite and energy metabolism. This review highlights the most recent advances in this field and discusses future research directions. We will examine the hormonal control of AMPK in the hypothalamus and discuss two key hypothalamic nuclei, the ARC and VMH. Finally, we will examine how AMPK regulates synaptic plasticity in the ARC to control appetite and energy homeostasis.