International Journal of Molecular Sciences Review Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights Kei-ichiro Inamori * and Jin-ichi Inokuchi * Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, Japan * Correspondence: [email protected] (K.-i.I.); [email protected] (J.-i.I.); Tel.: +81-22-727-0116 (K.-i.I.); +81-22-727-0117 (J.-i.I.) Received: 3 July 2020; Accepted: 26 July 2020; Published: 28 July 2020 Abstract: Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; Ugcg), GM3 synthase (GM3S; St3gal5), and GD3 synthase (GD3S; St8sia1) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling. Keywords: ganglioside; glycosphingolipid; leptin receptor signaling; hypothalamic neurons; energy homeostasis 1. Introduction Gangliosides (glycosphingolipids (GSLs) that contain one or more sialic acids) are essential components of membrane microdomains, and play key roles in a variety of important biological processes, including cell growth, differentiation, and signal transduction [1]. Ganglioside synthesis is initiated by addition of a glucose residue to the common precursor ceramide to form glucosylceramide (GlcCer) in the Golgi. Subsequently, a galactose residue is added to GlcCer to form lactosylceramide (LacCer), the precursor for synthesis of various ganglioside species and other types of GSLs (Figure1). GM3 synthase (GM3S, encoded by St3gal5) is a sialyltransferase that transfers sialic acid residue to LacCer via α2,3-linkage to form GM3 ganglioside. Based on GM3, GD3 synthase (GD3S, encoded by St8sia1) transfers sialic acid via α2,8-linkage to form the disialoganglioside GD3, and GM2 synthase (GM2S, encoded by B4galnt1) transfers N-acetylgalactosamine (GalNAc) to form GM2 (Figure1). GM2S can also act on LacCer and GD3 to generate GA2 and GD2, respectively. Gangliosides are involved in functioning of numerous growth factor receptors and hormone receptors, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor receptor (c-Met), nerve growth factor receptor (TrkA), insulin receptor (InsR), and insulin-like growth factor 1 receptor (IGF1R) [2]. Recent studies Int. J. Mol. Sci. 2020, 21, 5349; doi:10.3390/ijms21155349 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5349 2 of 17 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 have demonstrated the essential roles of gangliosides in hypothalamic control of feeding and energy homeostasishypothalamic through control regulation of feeding of and leptin energy receptor homeostasis (LepR) through signaling. regulation of leptin receptor (LepR) signaling. FigureFigure 1. Biosynthetic 1. Biosynthetic pathway pathway of of ganglio-series ganglio-series gangliosides.gangliosides. GCS GCS (Ugcg (Ugcg), ),a glucosyltransferase, a glucosyltransferase, catalyzescatalyzes the the first first step step in synthesisin synthesis of of ganglio-series ganglio-series gangliosides. Subsequently, Subsequently, LacCerS LacCerS (B4galt5/6 (B4galt5) /6) adds a galactose residue onto GlcCer to form LacCer. GM3S (St3gal5) is a sialyltransferase required adds a galactose residue onto GlcCer to form LacCer. GM3S (St3gal5) is a sialyltransferase required for for initiation of synthesis of a- and b-series gangliosides. GD3S (St8sia1) is a sialyltransferase required initiation of synthesis of a- and b-series gangliosides. GD3S (St8sia1) is a sialyltransferase required for for synthesis of b-series gangliosides. Four species (GM1, GD1a, GD1b, GT1b) comprise the majority synthesis of b-series gangliosides. Four species (GM1, GD1a, GD1b, GT1b) comprise the majority of of total brain gangliosides in mammals. total brain gangliosides in mammals. 2. Leptin Receptor Signaling 2. Leptin Receptor Signaling Leptin, a 16-kDa peptide hormone produced mainly from adipose tissue, is essential for Leptin, a 16-kDa peptide hormone produced mainly from adipose tissue, is essential for maintenance of energy homeostasis and body weight [3]. Adiposity is strongly correlated with maintenancecirculating of leptin energy level. homeostasis Leptin acts as and a transm bodyitter weight of metabolic [3]. Adiposity information is strongly to the hypothalamus, correlated with circulatingwhich plays leptin critical level. roles Leptin in regulation acts as a of transmitter feeding, body of metabolicweight, and information energy expenditure to the hypothalamus, [4]. Several whichhypothalamic plays critical nuclei, roles inincluding regulation the of arcuate feeding, nu bodycleus weight, (ARC), andparaventricular energy expenditure nucleus [4(PVN),]. Several hypothalamicventromedial nuclei, hypothalamus including the(VMH), arcuate and nucleus lateral (ARC),hypothalamic paraventricular area (LH), nucleus are involved (PVN), in ventromedialcontrol of hypothalamusenergy homeostasis (VMH), [5]. and ARC lateral contains hypothalamic two interconnected area (LH),groups are of neurons involved that in express control long-form of energy homeostasisleptin receptor [5]. ARC (LepRb) contains and is two the interconnectedmain site of leptin groups activity of [6]. neurons The proopiomelanocortin that express long-form (POMC) leptin receptorneurons (LepRb) are satiety-promot and is the maining siteand of tonically leptin activity release [6α].-melanocyte-stimulating The proopiomelanocortin hormone (POMC) (α-MSH; neurons are satiety-promotingprocessed from POMC), and tonicallywhich binds release to melanocortinα-melanocyte-stimulating receptor 4 (MC4R) hormone in PVN and (α-MSH; certain processed other fromhypothalamic POMC), which nuclei, binds and to thereby melanocortin promotes receptor an anor 4ectic (MC4R) effect in and PVN energy and expenditure. certain other The hypothalamic agouti- related peptide (AgRP) neurons are hunger-promoting and release (i) AgRP, which competes with nuclei, and thereby promotes an anorectic effect and energy expenditure. The agouti-related peptide α-MSH for MC4R binding in a coordinated fashion to regulate feeding and energy balance, and (ii) (AgRP) neurons are hunger-promoting and release (i) AgRP, which competes with α-MSH for MC4R neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) for regulation of energy balance. LepRb is bindingexpressed in acoordinated in both the above fashion groups to of regulate neurons. feeding However, and postprandially energy balance, increased and (ii)circulating neuropeptide leptin Y (NPY)level and stimulatesγ-aminobutyric POMC acidneurons (GABA) (with forconsequent regulation α-MSH of energy release balance. and inhibition LepRb is of expressed feeding) inbut both the aboveinhibits groups AgRP ofneurons. neurons. Elevated However, leptin postprandially level typically increasedgenerates a circulating strong signal leptin that levelfunctions stimulates to POMCprevent neurons obesity, (with however, consequent such αeffect-MSH is releaseweak or and disrupted inhibition in already-obese of feeding) but subjects. inhibits Obese AgRP rodents neurons. Elevatedand humans leptin level display typically hyperleptinemia generates aand strong do signalnot respond that functions substantially to prevent to exogenous obesity, leptin however, suchadministration effect is weak [7,8]. or disrupted in already-obese subjects. Obese rodents and humans display hyperleptinemia and do not respond substantially to exogenous leptin administration [7,8]. Int. J. Mol. Sci. 2020, 21, 5349 3 of 17 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 17 Signaling from leptin is generated via binding to its receptor LepR, a transmembrane protein Signaling from leptin is generated via binding to its receptor LepR, a transmembrane protein belonging to the class I cytokine receptor family [6]. Mice that lack functional leptin or LepR (ob/ob, db/db) belonging to the class I cytokine receptor family [6]. Mice that lack functional leptin or LepR (ob/ob, are hyperphagic and display severe obesity with hyperglycemia and insulin resistance [9]. Six LepR db/db) are hyperphagic and display severe obesity with hyperglycemia and insulin resistance [9]. Six isoforms (termed LepRa through LepRf) present in mice are generated from a single LepR gene by LepR isoforms (termed LepRa through LepRf) present in mice are generated