Hormone and glucose signalling in POMC and AgRP neurons

Abstract

In the wake of the obesity pandemic, increased research efforts are under way to define how peripheral hormones and metabolites regulate energy homeostasis. The melanocortin system, comprising anorexigenic proopiomelanocortin (POMC) expressing neurons and orexigenic agouti-related protein (AgRP)/neuropeptide Y (NPY) coexpressing neurons in the arcuate nucleus of the hypothalamus are crucial for normal energy homeostasis both in rodents and humans. They are regulated by peripheral hormones such as leptin and insulin, as well as nutrients such as glucose, amino acids and fatty acids. Although much progress has been made, recent reports continue to underline how restricted our understanding of POMC and AgRP/NPY neuron regulation by these signals is. Importantly, ATP-dependent potassium (K(ATP)) channels are regulated both by ATP (from glucose metabolism) and by leptin and insulin, and directly control electrical excitability of both POMC and AgRP neurons. Thus, this review attempts to offer an integrative overview about how peripheral signals, particularly leptin, insulin and glucose, converge on a molecular level in POMC and AgRP neurons of the arcuate nucleus of the hypothalamus to control energy homeostasis.

Figure 1. Direct and indirect models of glucose sensing

Glucose reaches neurons via cerebrospinal fluid or leaky blood–brain barrier. It is taken up directly by the neuron via a glucose transporter (GLUT), phosphorylated by glucose kinase (GK) and then metabolized to produce ATP, or it is taken up by astrocytes, converted to lactate, and then transported to neurons, where it is again used for ATP generation. ATP binds to and closes K_ATP channels, which leads to depolarization and an increase in firing. On the other hand, ATP generation decreases the AMP/ATP ratio, which leads to a decrease in AMPK activity. AMPK itself seems to be necessary for glucose sensing (at least in POMC and AgRP neurons), but it is unclear if gene expression, regulation of glucose transporters or other mechanisms contribute to that.

Figure 2. The role of PI3K and K_ATP channels in leptin and insulin signalling

Leptin and insulin both activate PI3K to induce either depolarization (leptin) or hyperpolarization (insulin). It is unclear how activation of the same signalling cascade leads to the two contrary outcomes, but subtle differences in activation strength and/or duration may contribute. Moreover, regulation of actin filaments may be necessary for K_ATP channel activation. PI3K activation also induces nuclear export of FOXO1, and thus abrogates FOXO1's inhibition of POMC expression. STAT3 activation induced by leptin is the driving force behind POMC expression, and competes with FOXO1 to bind the POMC promoter. At the same time, leptin, either by cell autonomous or presynaptic mechanisms, controls synaptic input onto POMC neurons. AKT, protein kinase B; PI3K, phosphatidylinositol 3-kinase; IR, insulin receptor; ObRb, long (signalling) isoform of the leptin receptor; PIP₃, phosphatidylinositol-3,4,5-trisphosphate.

Figure 3. Hypothetical regulation of K_ATP channel subunit expression by hormones and nutrients

K_ATP channel subunits KIR6.1/6.2 and SUR1/2 have been shown to be regulated by glycaemia and hormones such as oestradiol and progesterone. Changes in subunit expression may lead to differences in neuronal response towards glucose, which ultimately affects peripheral glucose production, which again either reinforces or diminishes K_ATP channel subunit expression. Besides neuropeptide expression, acute adjustment of ion channel activity and synaptic plasticity, regulation of subunit expression might be essential for central homeostatic control. The factors crucially involved in the KIR/SUR expression are not understood and thus stated as ‘Factor X’. S, steroids.