Neuronal Expression of Glucosylceramide Synthase in Central Nervous System Regulates Body Weight and Energy Homeostasis

Nordström, Viola; Willershäuser, Monja; Herzer, Silke; Rozman, Jan; Halbach, Oliver von Bohlen und; Meldner, Sascha; Rothermel, Ulrike; Kaden, Sylvia; Roth, Fabian C.; Waldeck, Clemens; Gretz, Norbert; Angelis, Martin Hrabé de; Draguhn, Andreas; Klingenspor, Martin; Gröne, Hermann Josef; Jennemann, Richard

doi:10.1371/journal.pbio.1001506

Cited by 59 publications

(87 citation statements)

References 73 publications

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“…GCS deletion by tamoxifen injection at the age of 6 weeks resulted in the development of marked obesity because of increased fat mass, hypometabolism, decreased sympathetic nervous activity, hypothermia, and glucose intolerance, as described earlier by us (18).…”

supporting

confidence: 63%

“…Ugcgf/f//CamKCreERT2 mice were generated as previously described (16,18,23). Mice were induced with tamoxifen 6 weeks after birth (18).…”

Section: Micementioning

confidence: 99%

“…Mice were induced with tamoxifen 6 weeks after birth (18). Experiments were performed in overnight (o/n)-fasted females at the age of 3-9 weeks after tamoxifen induction (postinduction [pi]), as stated in the figure legends.…”

Section: Micementioning

confidence: 99%

“…For MBH analysis, MBH of fasted insulin-injected (5 units/kg i.p., 15 min; Eli Lilly) mice was collected and processed as previously described (18). For WAT analysis, WAT was collected, shock frozen in liquid N 2 , and subsequently homogenized in RIPA buffer (12 mmol/L Na-deoxycholate, 1% NP-40 in PBS) containing proteinase inhibitor and phosphatase inhibitor cocktails (Roche).…”

Section: Western Blots and Immunoprecipitationmentioning

confidence: 99%

“…They contribute to the formation of membrane microdomains, regulating intracellular signal transduction (17). We have recently demonstrated (18) that adequate function of the hypothalamic leptin receptor (ObR) requires GCS expression.…”

mentioning

confidence: 99%

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Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase

et al. 2015

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Central nervous regulation of body weight and adipose tissue function is mainly conducted by hypothalamic neurons. Neuronal function depends on the integrity of the membrane lipid microenvironment. Lipid microdomains contain large quantities of cholesterol and glycosphingolipids, including glucosylceramide synthase (GCS) (gene Ugcg)-derived gangliosides. The current study demonstrates that Ugcgf/f//CamKCreERT2 mice with genetic GCS deletion in forebrain neurons, dominantly targeting mediobasal hypothalamus (MBH), display impaired fasting-induced lipolysis accompanied by a decreased norepinephrine content in white adipose tissue (WAT). MBH insulin receptor (IR) levels and signaling are increased in Ugcgf/f//CamKCreERT2 mice. These results are in concordance with reports stating that MBH insulin signaling restrains sympathetic nervous outflow to WAT in fasted mice. In line with the in vivo data, pharmacological GCS inhibition by Genz123346 also increases IR levels as well as IR phosphorylation in insulin-stimulated hypothalamic cells. In addition to studies suggesting that simple gangliosides like GM3 regulate peripheral IR signaling, this work suggests that complex neuronal gangliosides also modulate hypothalamic IR signaling and protein levels. For example, the complex ganglioside GD1a interacts dynamically with the IRs on adult hypothalamic neurons. In summary, our results suggest that neuronal GCS expression modulates MBH insulin signaling and WAT function in fasted mice.The central nervous system (CNS) balances energy intake to energy expenditure, termed body energy homeostasis. Among several other brain regions, the hypothalamic arcuate nucleus (Arc) harbors first-order neurons sensing peripheral energy signals, such as leptin and insulin (1,2). Subsequently, these neurons adapt energy intake to the energy needs of the body by altering their firing pattern and neurotransmitter expression (1-3).Most hypothalamic neuronal subpopulations possess receptors for the energy signals leptin and insulin. In the CNS, both hormones exert anorexic actions by suppressing food intake (4,5). Many reports (6,7) support the hypothesis that hypothalamic insulin and leptin systems act in a concerted manner in order to regulate feeding and glucose homeostasis, as well as body weight. In line with this, a novel concept of hypothalamic insulin/leptin cross talk demonstrates that leptin receptor signaling regulates mitochondrial function in hypothalamic neurons, which directly influences their insulin sensitivity (8). In the hypothalamic Arc, leptin signaling depolarizes anorexigenic proopiomelanocortin (POMC) neurons (3) and hyperpolarizes Agouti-related peptide (AgRP) neurons (9), thereby regulating energy homeostasis and body weight. In addition, central insulin signaling is an important regulator of peripheral glucose homeostasis and fat tissues (10,11). Signaling pathways for leptin and insulin converge on insulin receptor (IR) substrate/phosphatidylinositol 3 kinase (PI3K) in hypothalamic neurons (6,7). It has, however, also ...

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supporting

confidence: 63%

“…Ugcgf/f//CamKCreERT2 mice were generated as previously described (16,18,23). Mice were induced with tamoxifen 6 weeks after birth (18).…”

Section: Micementioning

confidence: 99%

Section: Micementioning

confidence: 99%

Section: Western Blots and Immunoprecipitationmentioning

confidence: 99%

mentioning

confidence: 99%

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Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase

et al. 2015

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Emerging concepts of ganglioside metabolism

Sandhoff

2018

FEBS Letters

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Gangliosides (GGs) are sialic acid-containing glycosphingolipids (GSLs) and major membrane components enriched on cellular surfaces. Biosynthesis of mammalian GGs starts at the cytosolic leaflet of endoplasmic reticulum (ER) membranes with the formation of their hydrophobic ceramide anchors. After intracellular ceramide transfer to Golgi and trans-Golgi network (TGN) membranes, anabolism of GGs, as well as of other GSLs, is catalyzed by membrane-spanning glycosyltransferases (GTs) along the secretory pathway. Combined activity of only a few promiscuous GTs allows for the formation of cell-type-specific glycolipid patterns. Following an exocytotic vesicle flow to the cellular plasma membranes, GGs can be modified by metabolic reactions at or near the cellular surface. For degradation, GGs are endocytosed to reach late endosomes and lysosomes. Whereas membrane-spanning enzymes of the secretory pathway catalyze GSL and GG formation, a cooperation of soluble glycosidases, lipases and lipid-binding cofactors, namely the sphingolipid activator proteins (SAPs), act as the main players of GG and GSL catabolism at intralysosomal luminal vesicles (ILVs).

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Glycolipids in Parkinson's disease: beyond neuronal function

Spanos

Deleidi

2023

FEBS Open Bio

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Glycolipid balance is key to normal body function, and its alteration can lead to a variety of diseases involving multiple organs and tissues. Glycolipid disturbances are also involved in Parkinson's disease (PD) pathogenesis and aging. Increasing evidence suggests that glycolipids affect cellular functions beyond the brain, including the peripheral immune system, intestinal barrier, and immunity. Hence, the interplay between aging, genetic predisposition, and environmental exposures could initiate systemic and local glycolipid changes that lead to inflammatory reactions and neuronal dysfunction. In this review, we discuss recent advances in the link between glycolipid metabolism and immune function and how these metabolic changes can exacerbate immunological contributions to neurodegenerative diseases, with a focus on PD. Further understanding of the cellular and molecular mechanisms that control glycolipid pathways and their impact on both peripheral tissues and the brain will help unravel how glycolipids shape immune and nervous system communication and the development of novel drugs to prevent PD and promote healthy aging.

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Neuronal Expression of Glucosylceramide Synthase in Central Nervous System Regulates Body Weight and Energy Homeostasis

Abstract: Body weight and energy homeostasis are regulated by leptin receptor interactions with gangliosides, a class of plasma membrane lipids, in forebrain neurons of mice.

Cited by 59 publications

References 73 publications

Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase

Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase

Emerging concepts of ganglioside metabolism

Glycolipids in Parkinson's disease: beyond neuronal function

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