Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals

Abstract

Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding “non-neuronal” cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed.

The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system

“…Although we and others have reported ACBP expression in neurons (32,48), ACBP is highly enriched in non-neuronal cells of the hypothalamus including ependymocytes, astrocytes, and tanycytes (31)(32)(33). Accumulating evidence suggests that tanycytes (49) and astrocytes play a key role in energy homeostasis (50). Observations of heightened susceptibility to diet-induced obesity in ACBP GFAP KO mice (loss of function in astrocytes, ependymocytes, and tanycytes), but not in ACBP Nkx2.1 KO mice (loss of function in neurons, ependymocytes, and tanycytes), that was reversed by restoration of ACBP expression in ARC GFAP + astrocytes firmly suggest that ACBP in ARC astrocytes regulates energy balance.…”

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

“…Therefore, it is plausible that disrupted neuronastrocyte metabolic interactions lead to blunted neurovascular coupling, even with preserved glucose sensing at cellular level. On the other hand, astrocytes are also direct sensors for glucose and fatty acids (Freire-Regatillo et al, 2017), leptin (Hsuchou et al, 2009) and insulin (Cai et al, 2018). Importantly, astrocytic insulin signalling plays a role in glucose-induced neuronal activation (García-Cáceres et al, 2016), and obesity impacts astrocyte functions (Hsuchou et al, 2009;Cai et al, 2018;García-Cáceres et al, 2016;Douglass et al, 2017).…”

“…Importantly, astrocytic insulin signalling plays a role in glucose-induced neuronal activation (García-Cáceres et al, 2016), and obesity impacts astrocyte functions (Hsuchou et al, 2009;Cai et al, 2018;García-Cáceres et al, 2016;Douglass et al, 2017). Loss of astrocytic glucose sensing in the hypothalamus may play a role in obesity and T2D development (Freire-Regatillo et al, 2017).…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…Importantly, these effects extend to astrocytes. For example, the in vivo reduction in increased PPAR levels in astrocytes reduces mitochondrial dysfunction, decreases inflammation, and increases cellular antioxidant defences [139][140][141]. These data are also of importance from the perspective of improving astrocyte function as all these factors are also involved in driving and maintaining a reactive state in these glial cells [142].…”