Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

Libby, Andrew E.; Wang, Hong; Mittal, Richa; Sungelo, Mitchell; Potma, Eric O.; Eckel, Robert H.

doi:10.1016/j.bbrc.2015.08.026

Cited by 17 publications

(18 citation statements)

References 27 publications

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“…In our mouse model, we also found changes in AGRP immunoreactivity in the hypothalamus that might be a consequence of reduced lipid storage in the microenvironment as a result of the LPL deletion in astrocytes. Indeed, Libby et al (34) reported that LPL is able to modulate AGRP level by regulating lipid storage in neurons. In addition to ceramide-induced lipid toxicity, we also observed elevation of ER stress markers and increased microglial immunoreactivity in the hypothalamus, both of which are associated with ceramide accumulation, as reported in other studies (31,32).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity

et al. 2017

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“…Nonetheless, we have recently shown that lipoprotein lipase (LPL), the rate-limiting enzyme in the hydrolysis of lipoprotein-derived FAs, may facilitate the uptake of FAs into dissociated hypothalamic neurons (39). Moreover, mice with a specific neuronal LPL deficiency exhibit a defect in nutrient sensing and become hyperphagic, relatively inactive and obsessed compared to WT control mice (40).…”

Section: Neuronal Uptake Of Lipids and Fasmentioning

confidence: 99%

Lipid Processing in the Brain: A Key Regulator of Systemic Metabolism

2017

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Metabolic disorders, particularly aberrations in lipid homeostasis, such as obesity, type 2 diabetes mellitus, and hypertriglyceridemia often manifest together as the metabolic syndrome (MetS). Despite major advances in our understanding of the pathogenesis of these disorders, the prevalence of the MetS continues to rise. It is becoming increasingly apparent that intermediary metabolism within the central nervous system is a major contributor to the regulation of systemic metabolism. In particular, lipid metabolism within the brain is tightly regulated to maintain neuronal structure and function and may signal nutrient status to modulate metabolism in key peripheral tissues such as the liver. There is now a growing body of evidence to suggest that fatty acid (FA) sensing in hypothalamic neurons via accumulation of FAs or FA metabolites may signal nutritional sufficiency and may decrease hepatic glucose production, lipogenesis, and VLDL-TG secretion. In addition, recent studies have highlighted the existence of liver-related neurons that have the potential to direct such signals through parasympathetic and sympathetic nervous system activity. However, to date whether these liver-related neurons are FA sensitive remain to be determined. The findings discussed in this review underscore the importance of the autonomic nervous system in the regulation of systemic metabolism and highlight the need for further research to determine the key features of FA neurons, which may serve as novel therapeutic targets for the treatment of metabolic disorders.

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“…For example, hypothalamic lipoprotein lipase, which promotes lipid uptake by hypothalamic neurons, has been demonstrated to enhance brain lipid sensing and to play a role in the regulation of energy balance [141,142] . Angiopoietin-like protein 3 significantly stimulates hypothalamic lipoprotein lipase activity, exhorting anorexia and weight loss, a mechanism which could be induced or commanded by leptin [143,144] .…”

Section: From Hypothalamic Lipid Metabolism To Whole Body Energy Homementioning

confidence: 99%

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

et al. 2016

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Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase and AMP-activated protein kinase, impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues not suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases such as insulin resistance, cardiomyopathy, atherosclerosis, and steatohepatitis. Current data have reported that, similar to what is observed in peripheral tissues, complex lipids such as ceramides and sphingolipids act as lipotoxic species at the hypothalamic level to impact metabolism. Here, we will review what is currently known about hypothalamic lipid metabolism and the modulation of energy homeostasis.

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Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

Cited by 17 publications

References 27 publications

Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity

Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity

Lipid Processing in the Brain: A Key Regulator of Systemic Metabolism

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

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