Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity

Abstract

Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism.

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

“…Body weight was significantly increased at week 10 while energy expenditure (light phase) was reduced in chow-fed ACBP GFAP KO male mice without changes in cumulative food intake, respiratory exchange ratio (RER), and locomotor activity as compared with controls (Supplemental Figure 2, C-G). Based on accumulating evidence suggesting a key role of hypothalamic astrocytes in feeding in response to leptin (18,35) and fatty acids (19,22), we tested whether astroglial ACBP is involved in the anorectic action of these signals. The anorectic response to central leptin was similar in ACBP GFAP KO males and control littermates (Supplemental Figure 2H).…”

“…Importantly, astrocytes have recently emerged as key players in the central response to metabolic signals and the control of energy balance (12), and obesity (13). Modulating the capacity of hypothalamic astrocytes to sense hormones and nutrients impairs glucose homeostasis (14)(15)(16)(17) and feeding (18), and contributes to diet-induced obesity (19). Recent studies suggest that metabolites secreted by astrocytes such as lactate (20,21), ketones (22,23), or adenosine (10,24) modulate the activity of hypothalamic neurocircuits.…”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…For example, astrocytes produce cholesterol (Camargo et al, ; Goritz, Mauch, & Pfrieger, ; Mauch et al, ; van Deijk et al, ) and actively elongate and desaturate fatty acid precursors in order to synthesize and release PUFAs (Green & Yavin, ; Moore, ; Moore, Yoder, Murphy, Dutton, & Spector, ). Furthermore, astrocyte lipid uptake via lipoprotein lipase is crucial for body weight control and the regulation of energy homeostasis (Gao et al, ).…”

Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism

“…Astrocytes can also metabolise many of the peripheral signals that they transport, such as glucose to lactate, thus controlling and modifying external messages reaching the surrounding neurones and directly influencing their responses. Although many of these functions have been discovered and studied in regard to astrocytic functions in disease process such as Alzheimer's or Parkinson's diseases, they have also come into the limelight in the field of neuroendocrinology for their implication in the perpetuation of weight gain and development of complications of obesity . Indeed, a better understanding of the role of these glial cells in the physiological control of metabolism would undoubtedly lead to a clearer vision of the processes that lead to comorbidities such as type 2 diabetes and cardiovascular dysfunction in obesity.…”