Hypothalamic neuronal-glial crosstalk in metabolic disease

Abstract

Metabolic diseases such as obesity and type 2 diabetes affect >2 billion people worldwide, yet there are currently no effective treatments to promote remission of disease. It is therefore critical to understand the physiological and pathophysiological mechanisms underlying metabolic disease, to drive the development of effective therapeutics. Whilst the majority of research over the past few decades has focused on neurons in the hypothalamus, there is growing evidence that non-neuronal glial cells in this region play a substantial role in regulating metabolism. Here, we provide an overview of the current dogmatic view of the neuroendocrine axis governing metabolism and update this neuron-centric view to include emerging evidence implicating glial cells including tanycytes, astrocytes, microglia, and oligodendrocyte lineage cells. We discuss the latest research implicating glia in hormone transport and hypothalamic inflammation, highlighting these cells as key contributors to metabolic control and dysfunction. Glial cells therefore offer new cellular and molecular targets for future therapeutic design, to tackle metabolic disease treatment from a new perspective.

Fig. 1. The neuroendocrine axis of metabolism.

Hormones released from the stomach (ghrelin), white adipose tissue (leptin) and pancreas (insulin) are released into the bloodstream and circulate to the brain to activate proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons within the arcuate nucleus of the hypothalamus. Activation of these neurons regulates food intake, energy expenditure and glucose metabolism. Insulin and leptin have anorexigenic effects by inhibiting AgRP neurons and activating POMC neurons, to promote secretion of POMC-derived melanocortins, which then bind to MC3R/MC4R on secondary neurons to reduce food intake and increase energy expenditure. Conversely, orexigenic ghrelin inhibits POMC neurons, and activates AgRP neurons to secrete appetite-stimulating peptides including AgRP, a MC3R/MC4R antagonist. AgRP neurons also release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and neuropeptide Y (NPY), which binds to Y1 and Y5 receptors, to inhibit POMC neurons and downstream satiety neurons.

Fig. 2. Glia drive neuroinflammation in the obese brain.

In the hypothalamus of lean mice (left), glial cells including astrocytes, microglia, nerve-glial antigen 2 (NG2)/oligodendrocyte precursor cells (OPCs), pericytes and tanycytes facilitate healthy physiological function by regulating metabolic hormone transport and neuronal function. In contrast, the obese brain is characterised by hypothalamic inflammation, driven by a phenomenon called reactive gliosis. Hypothalamic astrocytes and microglia proliferate and adopt pro-inflammatory phenotypes which can lead to dysfunction of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons.