Glia: silent partners in energy homeostasis and obesity pathogenesis

Abstract

Body weight stability requires homeostatic regulation to balance energy intake and energy expenditure. Research on this system and how it is affected by obesity has largely focused on the role of hypothalamic neurons as integrators of information about long-term fuel storage, short-term nutrient availability and metabolic demand. Recent studies have uncovered glial cells as additional contributors to energy balance regulation and obesity pathogenesis. Beginning with early work on leptin signalling in astrocytes, this area of research rapidly emerged after the discovery of hypothalamic inflammation and gliosis in obese rodents and humans. Current studies have revealed the involvement of a wide variety of glial cell types in the modulation of neuronal activity, regulation of hormone and nutrient availability, and participation in the physiological regulation of feeding behaviour. In addition, one glial type, microglia, has recently been implicated in susceptibility to diet-induced obesity. Together, these exciting new findings deepen our understanding of energy homeostasis regulation and raise the possibility of identifying novel mechanisms that contribute to the pathogenesis of obesity.

Keywords: Astrocytes; Brain; Central nervous system; Diabetes; Energy homeostasis; Glia; Hypothalamus; Inflammation; Microglia; Obesity; Review.

Fig. 1

The degree of microgliosis in response to HFD feeding predicts metabolic outcome. (a) HFD-fed male mice and rats have an accumulation and activation of microglia and astrocytes (not shown) in the hypothalamus that correlates with weight gain. (b) Hypothalamic depletion of microglia in male mice using PLX5622, a CSF1R antagonist, decreases food intake in the context of high saturated fatty acid consumption. (c) Females are relatively resistant to diet-induced hypothalamic gliosis and obesity. (d) Female mice with Cx3cr1 deficiency (encoding the chemokine (C-X3-C motif) receptor 1 [CX3CR1]) manifest male-pattern hypothalamic microglial accumulation and activation, accompanied by a marked increase in DIO susceptibility (M. Dorfman, J. Douglass, J. Thaler, unpublished observation). 3V, third ventricle

Fig. 2

Astrocytes integrate peripheral nutrient and hormone signals to modulate neuronal activity and function. Astrocytes are critical in maintaining hypothalamic integrity and homeostasis. In addition to regulating neuronal activity through the provision of metabolic substrates and neurotransmitter reuptake, these cells participate in the acute regulation of food intake by peripheral energy cues, such as leptin and ghrelin (green text, increase; red text, decrease). They do this via cognate receptors on their cell surface, including the leptin receptor (lepR) and the growth hormone secretagogue receptor (GHSR) (solid arrow, action on astrocytes; dashed arrow, action on neurons). Astrocytes also contribute to glucose homeostasis regulation through coordination of CNS metabolism. Under HFD feeding or obese conditions, astrocytes become reactive and may contribute to hypothalamic dysfunction and hyperphagia (not shown). 3V, third ventricle; GLAST, glutamate aspartate transporter; GLT-1, glutamate transporter 1; IR, insulin receptor

Fig. 3

Tanycytes and NG2 glia contribute to the regulation of energy metabolism. Both tanycytes and polydendrocytes provide BBB stability at the median eminence, are local sources of neural progenitors and regulate leptin signalling. In addition to these common properties, the two cell types have several unique functions. (a) Tanycytes directly regulate access of circulating hormones and nutrients into the brain parenchyma. (b) NG2 glia are important precursors of oligodendrocytes and provide trophic support to protect and maintain the processes of leptin-responsive neurons. 3V, third ventricle; + indicates stimulation